Polyvalent functionalized nanoparticle-based in vivo diagnostic system

ABSTRACT

A system for modulating a response signal includes polyvalent functionalized nanoparticles configured to bind with target analytes located on a surface of a cell, a detector configured to detect an analyte response signal transmitted from the body, a modulation source configured to modulate the analyte response signal, and a processor configured to non-invasively detect the one or more target analytes by differentiating the analyte response signal from a background signal, at least in part, based on the modulation. The analyte response signal is related to the binding interaction of the target analytes on the cell surface with the polyvalent functionalized nanoparticles. In some examples, the system may also include magnetic particles and a magnetic field source sufficient to distribute the magnetic particles into a spatial arrangement in the body. The analyte response signal may be differentiated from the background signal, at least in part, based on modulation of the signals due, at least in part, to the spatial arrangement of the magnetic particles.

BACKGROUND

Unless otherwise indicated herein, the materials described in thissection are not prior art to the claims in this application and are notadmitted to be prior art by inclusion in this section.

A number of scientific methods have been developed in the medical fieldto evaluate physiological conditions of a person by detecting and/ormeasuring one or more analytes in a person's blood or other bodilyfluids or tissues. The one or more analytes could be any analytes that,when present in or absent from the blood, or present at a particularconcentration or range of concentrations, may be indicative of a medicalcondition or health state of the person. The one or more analytes couldinclude enzymes, reagents, hormones, proteins, cells or other molecules,such as carbohydrates, e.g., glucose.

In a typical scenario, a person's blood is drawn and either sent to alab or input into a handheld testing device, such as a glucose meter,where one or more tests are performed to measure various analyte levelsand parameters in the blood. For most people, the blood tests areinfrequent, and an abnormal analyte level indicative of a medicalcondition may not be identified until the next blood test is performed.Even in the case of relatively frequent blood testing, such as may befound with those with diabetes, who regularly draw blood to test forblood glucose concentration, those blood tests are typically performedwhen the user is awake, although the blood glucose levels (and potentialvariations in such levels) occurring during the night could provideimportant information to assist a physician in assessing that person'smedical condition. Further, most known methods of analyte detection andanalysis require the collection of blood or other bodily fluid samples,which may be inconvenient, invasive and require significant patientcompliance.

Moreover, some blood analytes are particularly difficult to identify andquantify with conventional sensing techniques. For small or rarifiedanalytes, such as circulating tumor cells, for example, only 1 such cellmay be present in 10 mL of blood. Impractically large quantities ofblood would have to be drawn or otherwise sampled and analyzed in orderto catch such cells with statistical significance.

Methods for analyte detection and characterization often suffer from alow signal-to-noise ratio (SNR), since the signal obtained from theanalyte (in general, a small object) is typically weak in comparison tothe background. This can make discerning between target analytes presentin the blood, versus other analytes, particles, and tissues, etc.present in the blood and elsewhere in the body can be very difficult,especially where the measurements are taken non-invasively from outsidethe body. This is particularly true with some methods of analytecharacterization, such as optical methods, or where the target analytesare rare in the blood or are of a relatively small size. Accordingly,such measurements can be much more time consuming (if a large volume ofblood must be analyzed), less sensitive, less specific and generallyless informative on the whole. For example, with fluorescence detectiontechniques, it is often difficult to obtain highly sensitivemeasurements of a target analyte because other tissues, cells, andmolecules in the body may have some inherent fluorescent properties,creating a high level of background noise.

SUMMARY

Some embodiments of the present disclosure provide a system including:(i) polyvalent functionalized nanoparticles, wherein the polyvalentfunctionalized nanoparticles are configured to bind with one or moretarget analytes on a surface of a cell present in an environment; (ii) adetector configured to detect an analyte response signal transmittedfrom the environment, wherein the analyte response signal is related tobinding of the one or more target analytes on the cell surface with thepolyvalent functionalized nanoparticles; (iii) a modulation sourceconfigured to modulate the analyte response signal; and (iv) a processorconfigured to non-invasively detect the one or more target analytes onthe cell surface by differentiating the analyte response signal from abackground signal, at least in part, based on the modulation. Otherembodiments of the present disclosure provide a system including: (i)polyvalent functionalized nanoparticles, wherein the polyvalentfunctionalized nanoparticles are configured to bind with one or moretarget analytes on a surface of a cell present in an environment; (ii) adetector configured to detect a response signal transmitted from theenvironment, wherein the response signal includes a background signaland an analyte response signal related to binding of the one or moretarget analytes with polyvalent functionalized nanoparticles; (iii)magnetic particles; (iv) a magnetic field source sufficient todistribute the magnetic particles into a spatial arrangement in theenvironment; and (v) a processor configured to non-invasively detect theone or more target analytes by differentiating the analyte responsesignal from the background signal, at least in part, based on modulationof the signals due, at least in part, to the spatial arrangement of themagnetic particles.

Further embodiments of the disclosure provide a method including: (i)introducing polyvalent functionalized nanoparticles into an environment,wherein the functionalized nanoparticles are configured to bind with oneor more target analytes on a surface of a cell present in theenvironment; (ii) detecting a response signal transmitted from theenvironment, wherein the response signal includes an analyte responsesignal is related to binding of the one or more target analytes with thepolyvalent functionalized nanoparticles and wherein the response signalis modulated; and (iii) detecting one or more target analytes bydifferentiating the analyte response signal from a background signal, atleast in part, based on the modulation.

These as well as other aspects, advantages, and alternatives, willbecome apparent to those of ordinary skill in the art by reading thefollowing detailed description, with reference where appropriate to theaccompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of an example wearable device.

FIG. 2A is a perspective top view of an example wrist-mounted device,when mounted on a wearer's wrist.

FIG. 2B is a perspective bottom view of an example wrist-mounted deviceshown in FIG. 2A, when mounted on a wearer's wrist.

FIG. 3A is a perspective bottom view of an example wrist-mounted device,when mounted on a wearer's wrist.

FIG. 3B is a perspective top view of an example wrist-mounted deviceshown in FIG. 3A, when mounted on a wearer's wrist.

FIG. 3C is a perspective view of an example wrist-mounted device shownin FIGS. 3A and 3B.

FIG. 4A is a perspective view of an example wrist-mounted device.

FIG. 4B is a perspective bottom view of an example wrist-mounted deviceshown in FIG. 4A.

FIG. 5 is a perspective view of an example wrist-mounted device.

FIG. 6 is a perspective view of an example wrist-mounted device.

FIG. 7 is a block diagram of an example system that includes a pluralityof wearable devices in communication with a server.

FIG. 8 is a functional block diagram of an example wearable device.

FIG. 9 is a functional block diagram of an example wearable device.

FIG. 10 is a flowchart of an example method for operating a wearabledevice.

FIG. 11A is side partial cross-sectional view of an examplewrist-mounted device, while on a human wrist.

FIG. 11B is side partial cross-sectional view of an examplewrist-mounted device, while on a human wrist.

FIG. 12A is side partial cross-sectional view of an examplewrist-mounted device, while on a human wrist.

FIG. 12B is side partial cross-sectional view of an examplewrist-mounted device, while on a human wrist.

FIG. 13A is side partial cross-sectional view of an examplewrist-mounted device, while on a human wrist.

FIG. 13B is side partial cross-sectional view of an examplewrist-mounted device, while on a human wrist.

FIG. 14 is a flowchart of an example method for using a wearable deviceto take real-time, high-density, non-invasive, in vivo measurements ofphysiological parameters.

FIG. 15 is a flowchart of an example method for using a wearable deviceto take real-time, high-density, non-invasive, in vivo measurements ofphysiological parameters, in particular steps for measuring one or moreanalytes in blood circulating in subsurface vasculature proximate to thewearable device.

FIG. 16 is a flowchart of an example method for using a wearable deviceto take real-time, high-density, non-invasive, in vivo measurements ofphysiological parameters.

FIG. 17A is side partial cross-sectional view of a wearable device,while on a human wrist, illustrating use of an example modulationsource.

FIG. 17B is side partial cross-sectional view of a wearable device,while on a human wrist, illustrating use of an example modulationsource.

FIG. 18 is a functional block diagram of an example system including awearable device and a remote device.

FIG. 19 is a flowchart of an example method for detecting one or moreanalytes by modulating an analyte response signal.

FIG. 20A is side partial cross-sectional view of an example wearabledevice, while on a human wrist, illustrating use of an examplemodulation source.

FIG. 20B is a top view of a mask for use in an example system formodulating an analyte response signal.

FIG. 20C is a side partial cross-sectional detail view of an examplewearable device, while on a human wrist, illustrating use of an examplemodulation source.

FIG. 21A is a side partial cross-sectional detail view of an examplewearable device, while on a human wrist, illustrating use of an examplemodulation source.

FIG. 21B is a graphical representation of an example modulated analyteresponse signal.

FIG. 22 is a flowchart of an example method for detecting one or moreanalytes by modulating an analyte response signal.

FIG. 23A is side partial cross-sectional view of an example wearabledevice, while on a human wrist, illustrating use of an examplemodulation source.

FIG. 23B is a side partial cross-sectional detail view of an examplewearable device, while on a human wrist, illustrating use of an examplemodulation source.

FIG. 24A is side partial cross-sectional view of an example wearabledevice, while on a human wrist, illustrating use of an examplemodulation source.

FIG. 24B is side partial cross-sectional view of an example wearabledevice, while on a human wrist, illustrating use of an examplemodulation source.

FIG. 25A is side partial cross-sectional view of an example wearabledevice, while on a human wrist, illustrating use of an examplemodulation source.

FIG. 25B is side partial cross-sectional view of an example wearabledevice, while on a human wrist, illustrating use of an examplemodulation source.

FIG. 26 is a flowchart of an example method for detecting one or moreanalytes by modulating an analyte response signal.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying figures, which form a part hereof. In the figures, similarsymbols typically identify similar components, unless context dictatesotherwise. The illustrative embodiments described in the detaileddescription, figures, and claims are not meant to be limiting. Otherembodiments may be utilized, and other changes may be made, withoutdeparting from the scope of the subject matter presented herein. It willbe readily understood that the aspects of the present disclosure, asgenerally described herein, and illustrated in the figures, can bearranged, substituted, combined, separated, and designed in a widevariety of different configurations, all of which are explicitlycontemplated herein.

Further, while embodiments disclosed herein make reference to use on orin conjunction with a living human body, it is contemplated that thedisclosed methods, systems and devices may be used in any environmentwhere non-invasive detection of an analyte is desired. The environmentmay be any living or non-living body or a portion thereof, a fluidconduit, a fluid reservoir, etc. For example, one of skill in the artwill recognize that the embodiments disclosed herein may be used tosense analytes present in a water system. Moreover, while the presentdisclosure describes embodiments for use in vivo, one of skill in theart will also recognize that in vitro applications are possible as well.Accordingly, the environment may also include a test tube or othervessel for holding a fluid.

I. Overview

A diagnostic system can non-invasively detect and measure a plurality ofphysiological parameters of a person, which can include any parametersthat may relate to the person's health. For example, the system couldinclude sensors for measuring blood pressure, pulse rate, skintemperature, etc. At least some of the physiological parameters may beobtained by the system non-invasively detecting and/or measuring one ormore analytes in blood circulating in subsurface vasculature. The one ormore analytes could be any analytes that, when present in or absent fromthe surface of the cell in the blood, or present at a particularconcentration or range of concentrations, may be indicative of a medicalcondition or health of the person. For example, the one or more analytescould include enzymes, hormones, proteins, cells or other molecules.

In an example embodiment, the system obtains at least some of thehealth-related information by detecting the binding or interaction of aclinically-relevant analyte to or with particles, for example,microparticles or nanoparticles, introduced into a lumen of thesubsurface vasculature that have been functionalized with an receptorthat has a specific affinity to bind to or interact with the specificanalyte. The term “binding” is understood in its broadest sense to alsoinclude a detectable interaction between the clinically relevant analyteon the surface of a cell and the polyvalent functionalized particles,e.g, polyvalent nanoparticle conjugates. The polyvalent nanoparticleconjugates can be introduced into the person's blood stream byinjection, ingestion, inhalation, transdermally, or in some othermanner.

The surfaces of cancer cells can include a variety of different targetanalytes. The type of target analytes and their surface ratios dependson the cancer cell type. By functionalizing particles with two or morereceptors that detect different target analytes present on the surfaceof specific cancer cells, it is possible to detect minute amounts ofcirculating cancer or tumor cells in blood. The particles can befunctionalized by covalently or otherwise attaching or associating twoor more receptors that specifically binds or otherwise interacts withtwo or more particular clinically-relevant analytes on a surface of thecell with a defined affinity to the target analytes. Other compounds ormolecules, such as fluorophores or autofluorescent or luminescentmarkers or non-optical contrast agents (e.g. acoustic impedancecontrast, RF contrast and the like), which may assist in interrogatingthe particles in vivo, may also be attached to the particles.

The particles can have a diameter that is less than about 20micrometers. In some embodiments, the particles have a diameter on theorder of about 10 nanometers to 1 micrometer. In further embodiments,small particles on the order of 10-100 nanometers in diameter may beassembled to form a larger “clusters” or “assemblies on the order of1-10 micrometers. Those of skill in the art will understand a “particle”in its broadest sense and that it may take the form of any fabricatedmaterial, a molecule, cryptophan, a virus, a phage, etc. Further, aparticle may be of any shape, for example, spheres, rods,non-symmetrical shapes, etc.

In some examples, the particles may also be magnetic and can be formedfrom a paramagnetic, super-paramagnetic or ferromagnetic material or anyother material that responds to a magnetic field. Alternatively, theparticles may also be made of non-magnetic materials such aspolystyrene. Where magnetic particles are used, the system may include amagnet that can direct into the portion of subsurface vasculature amagnetic field that is sufficient to manipulate-polyvalentfunctionalized magnetic particle conjugates in a lumen of that portionof subsurface vasculature, for example, to collect or slow down in acertain area. However, measurements may be taken without localized“collection” of the polyvalent functionalized particle conjugates. Thesystem may be configured to activate the magnetic periodically, such asat certain times of the day (e.g., every hour).

The system may further include one or more data collection systems forinterrogating, in a non-invasive manner, the polyvalent functionalizedparticle conjugates present in a lumen of the subsurface vasculature ina particular local area. In one example, the system includes a detectorconfigured to detect a response signal transmitted from a portion ofsubsurface vasculature. The response signal can include both an analyteresponse signal, which can be related to the interaction of the one ormore target analytes with the polyvalent functionalized particleconjugates, and a background noise signal. For example, the polyvalentfunctionalized particle conjugates may include a chemiluminescent markerconfigured to produce a response signal in the form of luminescenceradiation produced in response to a chemical reaction initiated, atleast in part, to the binding of the target analyte to the particle.

In some examples, the system may also include an interrogating signalsource for transmitting an interrogating signal that can penetrate intoa portion of subsurface vasculature, or another body system, and adetector for detecting a response signal that is transmitted from theportion of subsurface vasculature, or other body system, in response tothe interrogating signal. The interrogating signal can be any kind ofsignal that is benign to the patient, such as electromagnetic, magnetic,optic, acoustic, thermal, mechanical, electric and results in a responsesignal that can be used to measure a physiological parameter or, moreparticularly, that can detect the binding or interaction of theclinically-relevant analyte to the polyvalent functionalized particleconjugates. In one example, the interrogating signal is a radiofrequency (RF) signal and the response signal is a magnetic resonancesignal, such as nuclear magnetic resonance (NMR). In another example,where the polyvalent functionalized particle conjugates include afluorophore, the interrogating signal is an optical signal with awavelength that can excite the fluorophore and penetrate the skin orother tissue and subsurface vasculature (e.g., a wavelength in the rangeof about 500 to about 1000 nanometers), and the response signal isfluorescence radiation from the fluorophore that can penetrate thesubsurface vasculature and tissue to reach the detector. In anotherexample, where the polyvalent functionalized particle conjugates includean electrically conductive material or a magnetically lossy material,the interrogation signal may be a time-varying magnetic field or a radiofrequency (RF) electromagnetic signal, with sufficient signal power torapidly heat the particles. The response signal may be an acousticemission from the particles, caused by rapid thermal expansion of theparticles, or caused by cavitation of the liquid medium in contact withthe particles. As described above, in some cases, an interrogatingsignal may not be necessary to produce an analyte response signal.

Additionally, the system may further include a modulation sourceconfigured to modulate the analyte response signal. The modulationsource can be configured to modulate the analyte response signaldifferently than the background noise signal. To this end, themodulation may help to discern between the target analyte and,essentially, everything else in the body by, for example, increasing thesignal-to-noise ratio. Generally, the modulation may include anyspatial, temporal, spectral, thermal, magnetic, mechanical, electrical,acoustic, chemical, or electrochemical, etc. modulation technique or anycombination thereof.

In some scenarios, it may also be useful to detect and distinguish boththe analyte response signal—related to polyvalent functionalizedparticle conjugates bound to or interacting with target analyte(s)—andan “unbound” particle signal—related to polyvalent functionalizedparticle conjugates not bound to or interacting with target analyte(s).For example, in some measurement or characterization schemes, it may beuseful to determine the percentage of polyvalent functionalized particleconjugates introduced into the body that have bound to the targetanalyte. In such cases, the modulation source may be configured tomodulate the analyte response signal differently than the unboundparticle signal.

The elements of the system, namely the type of modulation, thetype/shape/materials of particles, types of receptors and targetanalytes may all be interrelated. Ultimately, the type of particle andreceptor used to detect a particular target analyte may depend, to someextent, on the characteristics of the target analyte (i.e., type, size,shape, affinities, etc.), the chosen type of modulation (i.e., spatial,spectral, thermal, magnetic, mechanical, chemical, etc.), and/or themode of interrogation (optical, acoustic, magnetic, RF, etc.).

Data collected by the detector may be sent to a processor for analysis.The processor may be configured to non-invasively detect the one or moretarget analytes by differentiating the analyte response signal from thebackground noise signal based, at least in part, on the modulation. Insome cases, the processor may further be configured to differentiate theanalyte response signal from the unbound particle signal. Further, theprocessor may be configured to determine the concentration of aparticular target analyte in the blood from, at least in part, theanalyte response signal. The detection and concentration data processedby the processor may be communicated to the patient, transmitted tomedical or clinical personnel, locally stored or transmitted to a remoteserver, the cloud, and/or any other system where the data may be storedor accessed at a later time.

The processor may be located on an external reader, which may beprovided as an external body-mounted device, such as a necklace,wristwatch, eyeglasses, a mobile phone, a handheld or personal computingdevice or some combination thereof. Data collected by the detector maybe transmitted to the external reader via a communication interface.Control electronics can wirelessly communicate the data to the externalreader by modifying the impedance of an antenna in communication withthe detector so as to characteristically modify the backscatter from theantenna. In some examples, the external reader can operate tointermittently interrogate the detector to provide a reading byradiating sufficient radiation to power the detector to obtain ameasurement and communicate the result. In this way, the external readercan acquire a series of analyte identification and concentrationmeasurements over time without continuously powering the detector and/orprocessor. The processor may also be provided at another location distalto the detector, and the detector data is communicated to the processorvia a wired connection, a memory card, a USB device or other knownmethod. Alternatively, the processor may be located proximal to thedetector and may be configured to locally analyze the data that itcollects and then transmit the results of the analysis to an externalreader or server.

The external reader may include a user interface, or may furthertransmit the collected data to a device with a user interface that canindicate the results of the data analysis. In this way, the personwearing, holding or viewing the device can be made aware of the analysisand/or potential medical conditions. The external reader may also beconfigured to produce an auditory or tactile (vibration) response toalert the patient of a medical condition. Further, the external readermay also be configured to receive information from the patient regardinghis/her health state, wellness state, activity state, nutrition intakeand the like, as additional input information to the processor. Forexample, the user may input a health or wellness state, such as,experiencing migraine symptoms, jittery, racing heart, upset stomach,feeling tired, activity state including types and duration of physicalactivity nutrition intake including meal timing and composition, andother parameters including body weight, medication intake, quality ofsleep, stress level, personal care products used, environmentalconditions, social activity, etc. Further, the reader may also receivesignals from one or more other detectors, such as a pedometer, heartrate sensor, blood pressure sensor, blood oxygen saturation level, bodytemperature, GPS or other location or positioning sensors, microphone,light sensor, etc.

The system may be configured to obtain data during pre-set measurementperiods or in response to a prompt. For example, the system may beconfigured to operate the detector and collect data once an hour. Inother examples, the system may be configured to operate the detector inresponse to a prompt, such as a manual input by the patient or aphysician. The system may also be configured to obtain data in responseto an internal or external event or combination of events, such asduring or after physical activity, at rest, at high pulse rates, high orlow blood pressures, cold or hot weather conditions, etc. In otherexamples, the system could operate the detector more frequently or lessfrequently, or the system could measure some analytes more frequentlythan others.

Data collected by the system may be used to notify the patient of, asdescribed above, analyte levels or of an existing or imminent medicalemergency. In some examples, the data may be used to develop anindividual baseline profile for the patient. The baseline profile mayinclude patterns for how one or more of the patient's analyte levelstypically change over time, such as during the course of a day, a week,or a month, or in response to consumption of a particular type offood/drug. The baseline profile, in essence, may establish “normal”levels of the measured analytes for the patient. Additional data,collected over additional measurement periods, may be compared to thebaseline profile. If the additional data is consistent with the patternsembodied in the baseline profile, it may be determined that thepatient's condition has not changed. On the other hand, if theadditional data deviates from the patterns embodied in the baselineprofile, it may be determined that the patient's condition has changed.The change in condition could, for example, indicate that the patienthas developed a disease, disorder, or other adverse medical condition ormay be at risk for a severe medical condition in the near future.Further, the change in condition could further indicate a change in thepatient's eating habits, either positively or negatively, which could beof interest to medical personnel. Further, the patient's baseline anddeviations from the baseline can be compared to baseline and deviationdata collected from a population of wearers of the devices.

When a change in condition is detected, a clinical protocol may beconsulted to generate one or more recommendations that are appropriatefor the patient's change in condition. For example, it may berecommended that the patient inject himself/herself with insulin, changehis/her diet, take a particular medication or supplement, schedule anappointment with a medical professional, get a specific medical test, goto the hospital to seek immediate medical attention, abstain fromcertain activities, etc. The clinical protocol may be developed based,at least in part, on correlations between analyte concentration andhealth state derived by the server, any known health information ormedical history of the patient, and/or on recognized standards of carein the medical field. The one or more recommendations may then betransmitted to the external reader for communication to the user via theuser interface.

Correlations may be derived between the analyte concentration(s)measured by the system and the health state reported by the patient. Forexample, analysis of the analyte data and the health state data mayreveal that the patient has experienced certain adverse healthconditions, such as a migraine or a heart attack, when an analytereaches a certain concentration. This correlation data may be used togenerate recommendations for the patient, or to develop a clinicalprotocol. Blood analysis may be complemented with other physiologicalmeasurements such as blood pressure, heart rate, body temperature etc.,in order to add to or enhance these correlations.

Further, data collected from a plurality of patients, including both theanalyte measurements and the indications of health state, may be used todevelop one or more clinical protocols used by the server to generaterecommendations and/or used by medical professionals to provide medicalcare and advice to their patients. This data may further be used torecognize correlations between blood analytes and health conditionsamong the population. Health professionals may further use this data todiagnose and prevent illness and disease, prevent serious clinicalevents in the population, and to update clinical protocols, courses oftreatment, and the standard of care.

The above described system may be implemented as a wearable device. Theterm “wearable device,” as used in this disclosure, refers to any devicethat is capable of being worn at, on or in proximity to a body surface,such as a wrist, ankle, waist, chest, ear, eye or other body part. Inorder to take in vivo measurements in a non-invasive manner from outsideof the body, the wearable device may be positioned on a portion of thebody where subsurface vasculature is easily observable, thequalification of which will depend on the type of detection system used.The device may be placed in close proximity to the skin or tissue, butneed not be touching or in intimate contact therewith. A mount, such asa belt, wristband, ankle band, headband, etc. can be provided to mountthe device at, on or in proximity to the body surface. The mount mayprevent the wearable device from moving relative to the body to reducemeasurement error and noise. Further, the mount may be an adhesivesubstrate for adhering the wearable device to the body of a wearer. Thedetector, modulation source, interrogation signal source (if applicable)and, in some examples, the processor, may be provided on the wearabledevice. In other embodiments, the above described system may beimplemented as a stationary measurement device to which a user must bebrought into contact or proximity with or as a device that may betemporarily placed or held against a body surface during one or moremeasurement periods.

It should be understood that the above embodiments, and otherembodiments described herein, are provided for explanatory purposes, andare not intended to be limiting.

Further, the term “medical condition” as used herein should beunderstood broadly to include any disease, illness, disorder, injury,condition or impairment—e.g., physiologic, psychological, cardiac,vascular, orthopedic, visual, speech, or hearing—or any situationrequiring medical attention.

II. Example Wearable Devices

A wearable device 100 can automatically measure a plurality ofphysiological parameters of a person wearing the device. The term“wearable device,” as used in this disclosure, refers to any device thatis capable of being worn at, on or in proximity to a body surface, suchas a wrist, ankle, waist, chest, or other body part. In order to take invivo measurements in a non-invasive manner from outside of the body, thewearable device may be positioned on a portion of the body wheresubsurface vasculature is easily observable, the qualification of whichwill depend on the type of detection system used. The device may beplaced in close proximity to the skin or tissue, but need not betouching or in intimate contact therewith. A mount 110, such as a belt,wristband, ankle band, etc. can be provided to mount the device at, onor in proximity to the body surface. The mount 110 may prevent thewearable device from moving relative to the body to reduce measurementerror and noise. In one example, shown in FIG. 1, the mount 110, maytake the form of a strap or band 120 that can be worn around a part ofthe body. Further, the mount 110 may be an adhesive substrate foradhering the wearable device 100 to the body of a wearer.

A measurement platform 130 is disposed on the mount 110 such that it canbe positioned on the body where subsurface vasculature is easilyobservable. An inner face 140 of the measurement platform is intended tobe mounted facing to the body surface. The measurement platform 130 mayhouse a data collection system 150, which may include at least onedetector 160 for detecting at least one physiological parameter. The atleast one physiological parameter could be any parameter that may relateto the health of the person wearing the wearable device. For example,the detector 160 could be configured to measure blood pressure, pulserate, respiration rate, skin temperature, etc. At least one of thedetectors 160 is configured to non-invasively measure one or moreanalytes in blood circulating in subsurface vasculature proximate to thewearable device. In a non-exhaustive list, detector 160 may include anyone of an optical (e.g., CMOS, CCD, photodiode), acoustic (e.g.,piezoelectric, piezoceramic), electrochemical (voltage, impedance),thermal, mechanical (e.g., pressure, strain), magnetic, orelectromagnetic (e.g., magnetic resonance) sensor. The components of thedata collection system 150 may be miniaturized so that the wearabledevice may be worn on the body without significantly interfering withthe wearer's usual activities.

In some examples, the data collection system 150 further includes asignal source 170 for transmitting an interrogating signal that canpenetrate the wearer's skin into the portion of subsurface vasculature,for example, into a lumen of the subsurface vasculature. Theinterrogating signal can be any kind of signal that is benign to thewearer, such as electromagnetic, magnetic, optic, acoustic, thermal,mechanical, and results in a response signal that can be used to measurea physiological parameter or, more particularly, that can detect thebinding of the clinically-relevant analyte to the polyvalentfunctionalized particle conjugates. In one example, the interrogatingsignal is an electromagnetic pulse (e.g., a radio frequency (RF) pulse)and the response signal is a magnetic resonance signal, such as nuclearmagnetic resonance (NMR). In another example, the interrogating signalis a time-varying magnetic field, and the response signal is anexternally-detectable physical motion due to the time-varying magneticfield. The time-varying magnetic field modulates the particles byphysical motion in a manner different from the background, making themeasier to detect. In a further example, the interrogating signal is anelectromagnetic radiation signal. In particular, the interrogatingsignal may be electromagnetic radiation having a wavelength betweenabout 400 nanometers and about 1600 nanometers. The interrogating signalmay, more particularly, comprise electromagnetic radiation having awavelength between about 500 nanometers and about 1000 nanometers. Insome examples, the polyvalent functionalized particle conjugates includea fluorophore. The interrogating signal may therefore be anelectromagnetic radiation signal with a wavelength that can excite thefluorophore and penetrate the skin or other tissue and subsurfacevasculature (e.g., a wavelength in the range of about 500 to about 1000nanometers), and the response signal is fluorescence radiation from thefluorophore that can penetrate the subsurface vasculature and tissue toreach the detector.

In some cases, an interrogating signal is not necessary to measure oneor more of the physiological parameters and, therefore, the wearabledevice 100 may not include a signal source 170. For example, thepolyvalent functionalized particle conjugates include an autofluorescentor luminescent marker, such as a fluorophore, that will automaticallyemit a response signal indicative of the binding of theclinically-relevant analyte to the polyvalent functionalized particleconjugates, without the need for an interrogating signal or otherexternal stimulus. In some examples, the polyvalent functionalizedparticle conjugates may include a chemiluminescent marker configured toproduce a response signal in the form of luminescence radiation producedin response to a chemical reaction initiated, at least in part, to thebinding of the target analyte to the particle.

A collection magnet 180 may also be included in the data collectionsystem 150. In such embodiments, the polyvalent functionalized particleconjugates may also be made of or be functionalized with magneticmaterials, such as ferromagnetic, paramagnetic, super-paramagnetic, orany other material that responds to a magnetic field. The collectionmagnet 180 is configured to direct a magnetic field into the portion ofsubsurface vasculature that is sufficient to cause polyvalentfunctionalized magnetic particle conjugates to collect in a lumen ofthat portion of subsurface vasculature. The magnet may be anelectromagnet that may be turned on during measurement periods andturned off when a measurement period is complete so as to allow themagnetic particles to disperse through the vasculature.

The wearable device 100 may also include a user interface 190 via whichthe wearer of the device may receive one or more recommendations oralerts generated either from a remote server or other remote computingdevice, or from a processor within the device. The alerts could be anyindication that can be noticed by the person wearing the wearabledevice. For example, the alert could include a visual component (e.g.,textual or graphical information on a display), an auditory component(e.g., an alarm sound), and/or tactile component (e.g., a vibration).Further, the user interface 190 may include a display 192 where a visualindication of the alert or recommendation may be displayed. The display192 may further be configured to provide an indication of the measuredphysiological parameters, for instance, the concentrations of certainblood analytes being measured.

In one example, the wearable device is provided as a wrist-mounteddevice, as shown in FIGS. 2A, 2B, 3A-3C, 4A, 5B, 6 and 7. Thewrist-mounted device may be mounted to the wrist of a living subjectwith a wristband or cuff, similar to a watch or bracelet. As shown inFIGS. 2A and 2B, the wrist mounted device 200 may include a mount 210 inthe form of a wristband 220, a measurement platform 230 positioned onthe anterior side 240 of the wearer's wrist, and a user interface 250positioned on the posterior side 260 of the wearer's wrist. The wearerof the device may receive, via the user interface 250, one or morerecommendations or alerts generated either from a remote server or otherremote computing device, or alerts from the measurement platform. Such aconfiguration may be perceived as natural for the wearer of the devicein that it is common for the posterior side 260 of the wrist to beobserved, such as the act of checking a wrist-watch. Accordingly, thewearer may easily view a display 270 on the user interface. Further, themeasurement platform 230 may be located on the anterior side 240 of thewearer's wrist where the subsurface vasculature may be readilyobservable. However, other configurations are contemplated.

The display 270 may be configured to display a visual indication of thealert or recommendation and/or an indication of the measuredphysiological parameters, for instance, the concentrations of certainblood analytes being measured. Further, the user interface 250 mayinclude one or more buttons 280 for accepting inputs from the wearer.For example, the buttons 280 may be configured to change the text orother information visible on the display 270. As shown in FIG. 2B,measurement platform 230 may also include one or more buttons 290 foraccepting inputs from the wearer. The buttons 290 may be configured toaccept inputs for controlling aspects of the data collection system,such as initiating a measurement period, or inputs indicating thewearer's current health state (i.e., normal, migraine, shortness ofbreath, heart attack, fever, “flu-like” symptoms, food poisoning, etc.).

In another example wrist-mounted device 300, shown in FIGS. 3A-3C, themeasurement platform 310 and user interface 320 are both provided on thesame side of the wearer's wrist, in particular, the anterior side 330 ofthe wrist. On the posterior side 340, a watch face 350 may be disposedon the strap 360. While an analog watch is depicted in FIG. 3B, one ofordinary skill in the art will recognize that any type of clock may beprovided, such as a digital clock.

As can be seen in FIG. 3C, the inner face 370 of the measurementplatform 310 is intended to be worn proximate to the wearer's body. Adata collection system 380 housed on the measurement platform 310 mayinclude a detector 382, a signal source 384 and a collection magnet 386.As described above, the signal source 384 and the collection magnet 386may not be provided in all embodiments of the wearable device.

In a further example shown in FIGS. 4A and 4B, a wrist mounted device400 includes a measurement platform 410, which includes a datacollection system 420, disposed on a strap 430. Inner face 440 ofmeasurement platform may be positioned proximate to a body surface sothat data collection system 420 may interrogate the subsurfacevasculature of the wearer's wrist. A user interface 450 with a display460 may be positioned facing outward from the measurement platform 410.As described above in connection with other embodiments, user interface450 may be configured to display data collected from the data collectionsystem 420, including the concentration of one or more measuredanalytes, and one or more alerts generated by a remote server or otherremote computing device, or a processor located on the measurementplatform. The user interface 420 may also be configured to display thetime of day, date, or other information that may be relevant to thewearer.

As shown in FIG. 5, in a further embodiment, wrist-mounted device 500may be provided on a cuff 510. Similar to the previously discussedembodiments, device 500 includes a measurement platform 520 and a userinterface 530, which may include a display 540 and one or more buttons550. The display 540 may further be a touch-screen display configured toaccept one or more input by the wearer. For example, as shown in FIG. 6,display 610 may be a touch-screen configured to display one or morevirtual buttons 620 for accepting one or more inputs for controllingcertain functions or aspects of the device 600, or inputs of informationby the user, such as current health state.

FIG. 7 is a simplified schematic of a system including one or morewearable devices 700. The one or more wearable devices 700 may beconfigured to transmit data via a communication interface 710 over oneor more communication networks 720 to a remote server 730. In oneembodiment, the communication interface 710 includes a wirelesstransceiver for sending and receiving communications to and from theserver 730. In further embodiments, the communication interface 710 mayinclude any means for the transfer of data, including both wired andwireless communications. For example, the communication interface mayinclude a universal serial bus (USB) interface or a secure digital (SD)card interface. Communication networks 720 may be any one of may be oneof: a plain old telephone service (POTS) network, a cellular network, afiber network and a data network. The server 730 may include any type ofremote computing device or remote cloud computing network. Further,communication network 720 may include one or more intermediaries,including, for example wherein the wearable device 700 transmits data toa mobile phone or other personal computing device, which in turntransmits the data to the server 730.

In addition to receiving communications from the wearable device 700,such as collected physiological parameter data and data regarding healthstate as input by the user, the server may also be configured to gatherand/or receive either from the wearable device 700 or from some othersource, information regarding a wearer's overall medical history,environmental factors and geographical data. For example, a user accountmay be established on the server for every wearer that contains thewearer's medical history. Moreover, in some examples, the server 730 maybe configured to regularly receive information from sources ofenvironmental data, such as viral illness or food poisoning outbreakdata from the Centers for Disease Control (CDC) and weather, pollutionand allergen data from the National Weather Service. Further, the servermay be configured to receive data regarding a wearer's health state froma hospital or physician. Such information may be used in the server'sdecision-making process, such as recognizing correlations and ingenerating clinical protocols.

Additionally, the server may be configured to gather and/or receive thedate, time of day and geographical location of each wearer of the deviceduring each measurement period. Such information may be used to detectand monitor spatial and temporal spreading of diseases. As such, thewearable device may be configured to determine and/or provide anindication of its own location. For example, a wearable device mayinclude a GPS system so that it can include GPS location information(e.g., GPS coordinates) in a communication to the server. As anotherexample, a wearable device may use a technique that involvestriangulation (e.g., between base stations in a cellular network) todetermine its location. Other location-determination techniques are alsopossible.

The server may also be configured to make determinations regarding theefficacy of a drug or other treatment based on information regarding thedrugs or other treatments received by a wearer of the device and, atleast in part, the physiological parameter data and the indicated healthstate of the user. From this information, the server may be configuredto derive an indication of the effectiveness of the drug or treatment.For example, if a drug is intended to treat nausea and the wearer of thedevice does not indicate that he or she is experiencing nausea afterbeginning a course of treatment with the drug, the server may beconfigured to derive an indication that the drug is effective for thatwearer. In another example, a wearable device may be configured tomeasure blood glucose. If a wearer is prescribed a drug intended totreat diabetes, but the server receives data from the wearable deviceindicating that the wearer's blood glucose has been increasing over acertain number of measurement periods, the server may be configured toderive an indication that the drug is not effective for its intendedpurpose for this wearer.

Further, some embodiments of the system may include privacy controlswhich may be automatically implemented or controlled by the wearer ofthe device. For example, where a wearer's collected physiologicalparameter data and health state data are uploaded to a cloud computingnetwork for trend analysis by a clinician, the data may be treated inone or more ways before it is stored or used, so that personallyidentifiable information is removed. For example, a user's identity maybe treated so that no personally identifiable information can bedetermined for the user, or a user's geographic location may begeneralized where location information is obtained (such as to a city,ZIP code, or state level), so that a particular location of a usercannot be determined.

Additionally or alternatively, wearers of a device may be provided withan opportunity to control whether or how the device collects informationabout the wearer (e.g., information about a user's medical history,social actions or activities, profession, a user's preferences, or auser's current location), or to control how such information may beused. Thus, the wearer may have control over how information iscollected about him or her and used by a clinician or physician or otheruser of the data. For example, a wearer may elect that data, such ashealth state and physiological parameters, collected from his or herdevice may only be used for generating an individual baseline andrecommendations in response to collection and comparison of his or herown data and may not be used in generating a population baseline or foruse in population correlation studies.

III. Example Electronics Platform for a Wearable Device

FIG. 8 is a simplified block diagram illustrating the components of awearable device 800, according to an example embodiment. Wearable device800 may take the form of or be similar to one of the wrist-mounteddevices 200, 300, 400, 500, 600, shown in FIGS. 2A-B, 3A-3C, 4A-4C, 5and 6. However, wearable device 800 may also take other forms, such asan ankle, waist, or chest-mounted device.

In particular, FIG. 8 shows an example of a wearable device 800 having adata collection system 810, a user interface 820, communication platform830 for transmitting data to a server, and processor(s) 840. Thecomponents of the wearable device 800 may be disposed on a mount 850 formounting the device to an external body surface where a portion ofsubsurface vasculature is readily observable.

Processor 840 may be a general-purpose processor or a special purposeprocessor (e.g., digital signal processors, application specificintegrated circuits, etc.). The one or more processors 840 can beconfigured to execute computer-readable program instructions 870 thatare stored in the computer readable medium 860 and are executable toprovide the functionality of a wearable device 800 described herein.

The computer readable medium 860 may include or take the form of one ormore non-transitory, computer-readable storage media that can be read oraccessed by at least one processor 840. The one or morecomputer-readable storage media can include volatile and/or non-volatilestorage components, such as optical, magnetic, organic or other memoryor disc storage, which can be integrated in whole or in part with atleast one of the one or more processors 840. In some embodiments, thecomputer readable medium 860 can be implemented using a single physicaldevice (e.g., one optical, magnetic, organic or other memory or discstorage unit), while in other embodiments, the computer readable medium860 can be implemented using two or more physical devices.

Data collection system 810 includes a detector 812 and, in someembodiments, a signal source 814. As described above, detector 812 mayinclude any detector capable of detecting at least one physiologicalparameter, which could include any parameters that may relate to thehealth of the person wearing the wearable device. For example, thedetector 812 could be configured to measure blood pressure, pulse rate,skin temperature, etc. At least one of the detectors 812 is configuredto non-invasively measure one or more analytes in blood circulating insubsurface vasculature proximate to the wearable device. In someexamples, detector 812 may include one or more of an optical (e.g.,CMOS, CCD, photodiode), acoustic (e.g., piezoelectric, piezoceramic),electrochemical (voltage, impedance), thermal, mechanical (e.g.,pressure, strain), magnetic, or electromagnetic (e.g., magneticresonance) sensor.

In some examples, the data collection system 810 further includes asignal source 814 for transmitting an interrogating signal that canpenetrate the wearer's skin into the portion of subsurface vasculature.In general, signal source 814 will generate an interrogation signal thatwill produce a responsive signal that can be detected by one or more ofthe detectors 812. The interrogating signal can be any kind of signalthat is benign to the wearer, such as electromagnetic, magnetic, optic,acoustic, thermal, mechanical, and results in a response signal that canbe used to measure a physiological parameter or, more particularly, thatcan detect the binding of the clinically-relevant analyte to thepolyvalent functionalized particle conjugates. In one example, theinterrogating signal is an electromagnetic pulse (e.g., a radiofrequency (RF) pulse) and the response signal is a magnetic resonancesignal, such as nuclear magnetic resonance (NMR). In another example,the interrogating signal is a time-varying magnetic field, and theresponse signal is an externally-detectable physical motion due to thetime-varying magnetic field. The time-varying magnetic field modulatesthe particles by physical motion in a manner different from thebackground, making them easier to detect. In a further example, theinterrogating signal is an electromagnetic radiation signal. Inparticular, the interrogating signal may be electromagnetic radiationhaving a wavelength between about 400 nanometers and about 1600nanometers. The interrogating signal may, more particularly, compriseelectromagnetic radiation having a wavelength between about 500nanometers and about 1000 nanometers. In examples where the polyvalentfunctionalized particle conjugates include a fluorophore, theinterrogating signal may therefore be an electromagnetic radiationsignal with a wavelength that can excite the fluorophore and penetratethe skin or other tissue and subsurface vasculature (e.g., a wavelengthin the range of about 500 to about 1000 nanometers), and the responsesignal is fluorescence radiation from the fluorophore that can penetratethe subsurface vasculature and tissue to reach the detector.

The program instructions 870 stored on the computer readable medium 860may include instructions to perform or facilitate some or all of thedevice functionality described herein. For instance, in the illustratedembodiment, program instructions 870 include a controller module 872,calculation and decision module 874 and an alert module 876.

The controller module 872 can include instructions for operating thedata collection system 810, for example, the detector 812 and signalsource 814. For example, the controller 872 may activate signal source814 and/or detector 812 during each of the pre-set measurement periods.In particular, the controller module 872 can include instructions forcontrolling the signal source 814 to transmit an interrogating signal atpreset measurement times and controlling the detector 812 to receivedata representative of response signals transmitted from the portion ofsubsurface vasculature in response to the interrogating signalstransmitted at the preset measurement times.

The controller module 872 can also include instructions for operating auser interface 820. For example, controller module 872 may includeinstructions for displaying data collected by the data collection system810 and analyzed by the calculation and decision module 874, or fordisplaying one or more alerts generated by the alert module 875.Further, controller module 872 may include instructions to executecertain functions based on inputs accepted by the user interface 820,such as inputs accepted by one or more buttons disposed on the userinterface.

Communication platform 830 may also be operated by instructions withinthe controller module 872, such as instructions for sending and/orreceiving information via a wireless antenna, which may be disposed onor in the wearable device 800. The communication interface 830 canoptionally include one or more oscillators, mixers, frequency injectors,etc. to modulate and/or demodulate information on a carrier frequency tobe transmitted and/or received by the antenna. In some examples, thewearable device 800 is configured to indicate an output from theprocessor by modulating an impedance of the antenna in a manner that isperceivable by a remote server or other remote computing device.

Calculation and decision module 872 may include instructions forreceiving data from the data collection system 810 in the form of aresponsive signal, analyzing the data to determine if the target analyteis present or absent, quantify the measured physiological parameter(s),such as concentration of a target analyte, and analyzing the data todetermine if a medical condition is indicated. In particular, thecalculation and decision module 872 may include instructions fordetermining, for each preset measurement time, a concentration of aclinically-relevant analyte based on the response signal detected by thedetector at that measurement time and determining, for each presetmeasurement time, whether a medical condition is indicated based on atleast the corresponding concentration of the clinically-relevantanalyte. The preset measurement times may be set to any period and, inone example, are about one hour apart.

The program instructions of the calculation and decision module 872 may,in some examples, be stored in a computer-readable medium and executedby a processor located external to the wearable device. For example, thewearable device could be configured to collect certain data regardingphysiological parameters from the wearer and then transmit the data to aremote server, which may include a mobile device, a personal computer,the cloud, or any other remote system, for further processing.

The computer readable medium 860 may further contain other data orinformation, such as medical and health history of the wearer of thedevice, that may be useful in determining whether a medical condition isindicated. Further, the computer readable medium 860 may contain datacorresponding to certain analyte baselines, above or below which amedical condition is indicated. The baselines may be pre-stored on thecomputer readable medium 860, may be transmitted from a remote source,such as a remote server, or may be generated by the calculation anddecision module 874 itself. The calculation and decision module 874 mayinclude instructions for generating individual baselines for the wearerof the device based on data collected over a certain number ofmeasurement periods. For example, the calculation and decision module874 may generate a baseline concentration of a target blood analyte foreach of a plurality of measurement periods by averaging the analyteconcentration at each of the measurement periods measured over thecourse of a few days, and store those baseline concentrations in thecomputer readable medium 860 for later comparison. Baselines may also begenerated by a remote server and transmitted to the wearable device 800via communication interface 830. The calculation and decision module 874may also, upon determining that a medical condition is indicated,generate one or more recommendations for the wearer of the device based,at least in part, on consultation of a clinical protocol. Suchrecommendations may alternatively be generated by the remote server andtransmitted to the wearable device.

In some examples, the collected physiological parameter data, baselineprofiles, health state information input by device wearers and generatedrecommendations and clinical protocols may additionally be input to acloud network and be made available for download by a wearer'sphysician. Trend and other analyses may also be performed on thecollected data, such as physiological parameter data and health stateinformation, in the cloud computing network and be made available fordownload by physicians or clinicians.

Further, physiological parameter and health state data from individualsor populations of device wearers may be used by physicians or cliniciansin monitoring efficacy of a drug or other treatment. For example,high-density, real-time data may be collected from a population ofdevice wearers who are participating in a clinical study to assess thesafety and efficacy of a developmental drug or therapy. Such data mayalso be used on an individual level to assess a particular wearer'sresponse to a drug or therapy. Based on this data, a physician orclinician may be able to tailor a drug treatment to suit an individual'sneeds.

In response to a determination by the calculation and decision module874 that a medical condition is indicated, the alert module 876 maygenerate an alert via the user interface 820. The alert may include avisual component, such as textual or graphical information displayed ona display, an auditory component (e.g., an alarm sound), and/or tactilecomponent (e.g., a vibration). The textual information may include oneor more recommendations, such as a recommendation that the wearer of thedevice contact a medical professional, seek immediate medical attention,or administer a medication.

FIG. 9 is a simplified block diagram illustrating the components of awearable device 900, according to an example embodiment. Wearable device900 is the same as wearable device 800 in all respects, except that thedata collection system 910 of wearable device 900 further includes acollection magnet 916. In this example, the collection magnet 916 may beused to locally collect polyvalent functionalized magnetic particlesconjugates present in an area of subsurface vasculature proximate to thecollection magnet 916. As described above, collection magnet 916 isconfigured to direct a magnetic field into a portion of subsurfacevasculature sufficient to cause the polyvalent functionalized magneticparticles conjugates to collect in a lumen of the portion of subsurfacevasculature.

Wearable device 900 includes a data collection system 910, whichincludes a detector 912, a signal source 914 (if provided) and acollection magnet 916, a user interface 920, a communication interface930, a processor 940 and a computer readable medium 960 on which programinstructions 970 are stored. All of the components of wearable device900 may be provided on a mount 950. In this example, the programinstructions 970 may include a controller module 962, a calculation anddecision module 964 and an alert module 966 which, similar to theexample set forth in FIG. 8, include instructions to perform orfacilitate some or all of the device functionality described herein.Controller module 962 further includes instructions for operatingcollection magnet 916. For example, controller module 962 may includeinstructions for activating collection magnet during a measurementperiod, for a certain amount of time.

IV. Illustrative Polyvalent Functionalized—Particle Conjugates

In some examples, the wearable devices described above obtain at leastsome of the health-related information by detecting the binding of aclinically-relevant analyte to polyvalent functionalized conjugatedparticles, also referred to as polyvalent functionalized particles. Itis known that many cells interact through multiple simultaneousmolecular contacts and therefore display a variety of ligands orbiomarkers on its surface including, without limitation, proteins,peptides, carbohydrates, antibodies and fragments thereof, lipids,toxins produced by pathogens, pathogen adhesion molecules, mammaliancell surface molecules, mammalian extracellular matrix molecules,glycopeptides, glycolipids, peptidolipids, fucopeptides and othermolecules. Representative biomarkers as target analytes include HER2,EGFR, EGFR1, CEA, VEGF, CD20, CD22 and CD52. Furthermore, depending onthe cell type, the biomarkers may be presented on cell surfaces invarious ratios. These biomarkers can be targeted by the polyvalentfunctionalized particles for detection of miniscule amounts of cellscirculating in blood or present in other bodily fluids.

The presentation of polyvalent binding receptors on the surface of theparticle can dramatically increase the avidity and/or specificity of thepolyvalent particle conjugate to a target analyte of interest such asproteins or other molecules on the surface of targeted cells, allowingfor cell-specific detection of tumors, metastases, nonvascularizedmalignant cell clusters, individual malignant cells as well as diseasedcells and cells infected with pathogens such as viruses, bacteria, fungiand parasites. Representative examples of cells that can be detectedinclude, without limitations, leukocytes, epithelial cells, endothelialcells, epidermal cells, neurons, red blood cells, tumor cells, endocrinecells, dendritic cells, M cells, stem cells, osteoblasts, osteocytes,bone marrow cells, and tissue macrophages.

The particles could be, for example, microparticles or nanoparticles.The particles can be functionalized by covalently attaching a variety oftwo or more receptors designed to selectively bind or otherwiserecognize a particular variety of clinically-relevant analytes presenton a cell surface. For example, particles may be functionalized with oneor more receptors to increase avidity to a target analyte or to detectmultiple different targets on a cell surface. Representative receptorsinclude, without limitation, antibodies, nucleic acids (DNA, siRNA), lowmolecular weight ligands (folic acid, thiamine, dimercaptosuccinicacid), peptides (RGD, LHRD, antigenic peptides, internalizationpeptides), proteins (BSA, transferrin, antibodies, lectins, cytokines,fibrinogen, thrombin), polysaccharides (hyaluronic acid, chitosan,dextran, oligosaccharides, heparin), polyunsaturated fatty acids(palmitic acid, phospholipids), plasmids, and aptamers. The polyvalentfunctionalized particle conjugates can be introduced into the person'sblood stream by injection, ingestion, inhalation, transdermally, or insome other manner.

The clinically-relevant analyte could be any analyte that, when presentin or absent from surfaces of cells in tissue or circulating in blood orpresent at a particular concentration or range of concentrations orratios, may be indicative of a medical condition or indicative that amedical condition may be imminent. For example, the clinically-relevantanalyte could be an enzyme, hormone, protein, or other molecule. In onerelevant example, certain biomarkers are known to be predictive of theexistence of a tumor or cancer or potential metathesis of cancer cellsto distant sites or an impending health condition. The presence of thesebiomarkers may be detected, and the medical condition treated, byproviding particles functionalized with two or more receptors that willselectively bind to target analytes on the surface of a cell.

The particles may be made of biodegradable or non-biodegradablematerials. For example, the particles may be made of polystyrene.Non-biodegradable particles may be provided with a removal means toprevent harmful buildup in the body. Generally, the particles may bedesigned to have a long half-life so that they remain in the vasculatureor body fluids over several measurement periods. Depending on thelifetime of the particles, however, the user of the wearable device mayperiodically introduce new batches of polyvalent functionalized particleconjugates into the vasculature or body fluids.

Nanoparticles have been the subject of considerable research interest,particularly in the fields of diagnostics and drug therapy.Nanoparticles are defined as particulate dispersions or solid particleswith a size ranging from 10 to 1000 nm. Nanoparticles can be synthesizedby a variety of methods including the sol-gel process, dispersion ofpreformed polymers, polymerization of monomers, ionic gelation orcoacervation of hydrophilic polymers and can be prepared from a varietyof materials include metals, proteins, polysaccharides, or syntheticpolymers. The selection of materials can be dependent on many factorsincluding (a) the size of the nanoparticles required; (b) desiredsurface characteristics such as charge and permeability; (c) degree ofbiodegradability, biocompatibility and toxicity; and (d) if thenanoparticle is used as a carrier to deliver a payload such as a drug,the inherent properties of the drug such as the aqueous solubility andstability.

Particle size and size distribution can be important characteristics ofnanoparticle systems as they determine the in vivo distribution,biological fate, toxicity and the targeting ability of the nanoparticlesystems. In addition, they can also influence the drug loading, drugrelease and stability of nanoparticles.

Particles such as nanoparticles can act as scaffolds for immobilizationof detection elements such as receptors, enhance electron transfer,catalyze electrochemical reactions or act as reactant themselves.Surface modification of nanoparticles can drastically improvebiocompatibility, half-life and biodistribution. The conjugation ofreceptors to nanoparticles allows for the detection and quantitation oftarget analytes on cell surfaces in vivo. The polyvalent particleconjugates can act as a binding agent, a molecular switch or both, tomeasure the in vivo levels of target analytes on cells of interest. Twoor more different receptors may be used to improve avidity to a targetanalyte or to create particles that can detect multiple different targetanalytes. The binding or release of the polyvalent functionalizednanoparticle conjugate to a target analyte in vivo can trigger aconformational change to cause a more stable confirmation that permitssubsequent binding of a detectable agent such as a fluorophore, increaseor decrease fluorescence via FRET, release/bind a secondary detectablemolecule, or cause targeted release of a molecular payload such as adrug, ion or a sensor. For polyvalent functionalized particle conjugatestargeted to a receptor on a cell surface, a conformational change mayoccur which can increase or decrease fluorescence via FRET, lead toendocytosis followed by a pH change that leads to a detectableconformational change of the receptor or lead to endocytosis followed bya pH change in the endosome which may be detected by a pH sensitive dye.

The receptors can be used in diagnostic procedures, or even in therapyto destroy a specific cell target, such as antitumor therapy or targetedchemotherapy. The particles can be designed to remove from the body ordestroy the target analyte once bound to the receptor. Additionalfunctional groups can be added to the particles to signal that theparticles can be removed from the body through the kidneys, for example,once bound to the target analyte.

Further, the particles may be designed to either releasably orirreversibly bind to the target analyte present on the cell surface. Forexample, if it is desired for the particles to participate indestruction or removal of a targeted cell from the body, as describedabove, the particles may be designed to irreversibly bind to thetargeted cell. In other examples, the particles may be designed torelease the target cell after measurement has been made, eitherautomatically or in response to an external or internal stimulus.

The polyvalent functionalized particle conjugates could also be used forin vivo enrichment and extraction of low abundance circulatingbiomarkers. For instance, the polyvalent functionalized conjugates canbe circulated and any biomolecules bound to the polyvalentfunctionalized conjugates may be eluted off and analyzed in vitro.

Those of skill in the art will understand the term “particle” in itsbroadest sense and that it may take the form of any fabricated material,a molecule, cryptophan, a virus, a phage, etc. Further, a particle maybe of any shape, for example, spheres, rods, non-symmetrical shapes,etc., and may be made of a solid, liquid or gaseous material orcombinations thereof. The particles can have a diameter that is lessthan about 20 micrometers. In some embodiments, the particles have adiameter on the order of about 10 nanometers to 1 micrometer. In furtherembodiments, small particles on the order of 10-100 nanometers indiameter may be assembled to form a larger “clusters” or “assemblies onthe order of 1-10 micrometers. In this arrangement, the assemblies wouldprovide the signal strength of a larger particle, but would bedeformable, thereby preventing blockages in smaller vessels andcapillaries.

Binding of the polyvalent functionalized particle conjugates to a targetanalyte may be detected with or without a stimulating signal input. Theterm “binding” is understood in its broadest sense to include anydetectable interaction between the receptor and the target analyte. Forexample, some particles may be functionalized with compounds ormolecules, such as fluorophores or autofluorescent, luminescent orchemiluminescent markers, which generate a responsive signal when theparticles bind to the target analyte without the input of a stimulus. Inother examples, the polyvalent functionalized particle conjugates mayproduce a different responsive signal in their bound versus unboundstate in response to an external stimulus, such as an electromagnetic,acoustic, optical, or mechanical energy.

Further, the particles may be formed from a paramagnetic orferromagnetic material or be functionalized with a magnetic moiety. Themagnetic properties of the particles can be exploited in magneticresonance detection schemes to enhance detection sensitivity. In anotherexample, an external magnet may be used to locally collect the particlesin an area of subsurface vasculature during a measurement period. Suchcollection may not only increase the differential velocity betweenparticles and analytes, hence surveying a much larger volume per unittime, but may also enhance the signal for subsequent detection.

Polyvalent functionalized conjugates can be prepared by any suitablemeans. For instance, aptamers have been developed that are specific fortarget analytes including cell types. See, for instance, K. Sefah et al.Nature Protocols, Vol. 5, pp. 1169-1185 (June 2010) describing aptamersspecific for any cell type and Q. Shen et al., Adv. Mater., Vol. 25, pp.2368-2373. DOI: 10.1002/adma.201300082, describing preparation ofaptamers specific for A549 non-small cell lung cancer cells, which areincorporated by reference in their entirety. Aptamers are also availablecommercially. See, for instance, OTCbiotechnologies, LLC, San Antonio,Tex., USA and Base Pair Biotechnologies, Inc., Houston, Tex., USA; andAMS biotechnology (Europe) LTD, Abingdon, UK.

Suitable particles including nanoparticles can be prepared by anysuitable means. See, for instance, Y. Deng et al., J. Magnetism andMagnetic Materials, Vol. 257, pp. 69-78 (February 2003) and W. Fang etal., J. Mater. Chem, 2010, Vol. 20, pp. 8624-8630DOI:10.1039/C0JM02081H, both describing preparation of polymericmagnetic particles, which references are incorporated by reference intheir entirety, Suitable particles including magnetic microparticles andnanoparticles are also available commercially. See, for instance,Chemicell GmBH, Berlin, Germany; and Ademtech Inc., New York, N.Y., USA.

Any suitable method for conjugating the aptamers or other types ofreceptors to a particle may be used. See, for instance, well-known clickchemistry be used which entails labeling the aptamer with an azide oralkyne group and coupling the labeled receptor, e.g., aptamer to analkyne/azide group on the particle. Alternatively, the receptor, e.g.,aptamer, may be labeled with an NH2 group and then coupled to —COOHgroup on the particle using1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC orEDAC) cross-linking agent (commercially available from Thermo FisherScientific, Inc., Rockford, Ill., USA). In addition, photocleavablelinkers or spacers can be used to conjugate the receptor e.g., aptamer,to a particle. Photocleavable linkers are commercially available. Seefor instance Integrated DNA Technologies, Inc., Coralville, Iowa, USA;and Ambergen, Inc., Watertown, Mass., USA).

V. Illustrative Methods for Operation of a Wearable Device

FIG. 10 is a flowchart of a method 1000 for operating a wearable deviceto take non-invasive, in vivo, real-time measurements of physiologicalparameters. A wearable device is first mounted to a body surface of ahuman subject, wherein the body surface is proximate to a portion ofsubsurface vasculature (1010). In some examples, the wearable device,via a signal source, transmits an interrogating signal into the portionof subsurface vasculature (1020). The wearable device, via a detector,then detects a response signal transmitted from the portion ofsubsurface vasculature, wherein the response signal is related tobinding of a clinically-relevant analyte to polyvalent functionalizedparticle conjugates present in a lumen of the subsurface vasculature(1030). In some examples, the response signal is generated in responseto an interrogating signal. The polyvalent functionalized particleconjugates are configured to bind to the clinically-relevant analyte andcomprise one or more types of receptor. The term “bind” is understood inits broadest sense to also include any detectable interaction betweenthe clinically relevant analyte and the polyvalent functionalizedparticle conjugates. The wearable device then determines the presence,absence and/or a concentration of the clinically-relevant analyte basedon the response signal (1040) and whether a medical condition isindicated based on at least the presence, absence and/or concentrationof the clinically-relevant analyte (1050). Further, in examples wherethe polyvalent functionalized particle conjugates are magnetic, thewearable device may further direct a magnetic field into the portion ofsubsurface vasculature, the magnetic field being sufficient to cause thepolyvalent functionalized magnetic particle conjugates to collect in alumen of the portion of subsurface vasculature.

FIGS. 11A-11B, 12A-12B, and 13A-13B are partial cross-sectional sideviews of a human wrist illustrating the operation of various examples ofa wrist-mounted device. In the example shown in FIGS. 11A and 11B, thewrist-mounted device 1100 includes a measurement platform 1110 mountedon a strap or wrist-band 1120 and oriented on the anterior side 1190 ofthe wearer's wrist. Measurement platform 1110 is positioned over aportion of the wrist where subsurface vasculature 1130 is easilyobservable. Polyvalent functionalized particle conjugates 1140 have beenintroduced into a lumen of the subsurface vasculature by one of themeans discussed above. In this example, measurement platform 1110includes a data collection system having both a detector 1150 and asignal source 1160. FIG. 11A illustrates the state of the subsurfacevasculature when measurement device 1100 is inactive. The state of thesubsurface vasculature during a measurement period is illustrated inFIG. 11B. At this time, signal source 1160 is transmitting aninterrogating signal 1162 into the portion of subsurface vasculature anddetector 1150 is receiving a response signal 1152 generated in responseto the interrogating signal 1162. The response signal 1152 is related tothe binding of a clinically relevant analyte present in the subsurfacevasculature to the polyvalent functionalized particle conjugates 1140.As described above, in some embodiments, an interrogating signal may notbe necessary to generate a response signal related to the binding of ananalyte to the polyvalent functionalized particle conjugates.

Similar to the system depicted in FIGS. 11A and 11B, FIGS. 12A and 12Billustrate a wrist-mounted device 1200 including a measurement platform1210 mounted on a strap or wristband 1220 and oriented on the anteriorside 1290 of the wearer's wrist. In this example, measurement platform1210 includes a data collection system having a detector 1250, a signalsource 1260 and a collection magnet 1270. FIG. 12A illustrates the stateof the subsurface vasculature when measurement device 1200 is inactive.The state of the subsurface vasculature when measurement device 1200 isactive during a measurement period is illustrated in FIG. 12B. At thistime, collection magnet 1270 generates a magnetic field 1272 sufficientto cause polyvalent functionalized magnetic particle conjugates 1240present in a lumen of the subsurface vasculature 1230 to collection in aregion proximal to the magnet 1270. Signal source 1260 transmits aninterrogating signal 1262 into the portion of subsurface vasculature anddetector 1250 is receiving a response signal 1252 generated in responseto the interrogating signal 1262. The response signal 1252 is related tothe binding of a clinically relevant analyte present in the subsurfacevasculature to the polyvalent functionalized magnetic particleconjugates 1240. As described above, in some embodiments, aninterrogating signal may not be necessary to generate a response signalrelated to the binding of an analyte to the polyvalentfunctionalized-magnetic particle conjugates.

FIGS. 13A and 13B illustrate a further embodiment of a wrist-mounteddevice 1300 having a measurement platform 1310 disposed on a strap 1320,wherein the detector 1350 and signal source 1360 are positioned on theposterior side 1390 of the wearer's wrist and the collection magnet 1370is disposed on the anterior side 1380 of the wearer's wrist. Similar tothe embodiments discussed above, FIG. 13A illustrates the state of thesubsurface vasculature when measurement device 1300 is inactive. Thestate of the subsurface vasculature when measurement device 1300 isactive during a measurement period is illustrated in FIG. 13B. At thistime, collection magnet 1370 generates a magnetic field 1232 sufficientto cause polyvalent functionalized-magnetic particle conjugates 1340present in a lumen of the subsurface vasculature 1330 to collection in aregion proximal to the magnet 1370. Signal source 1360 transmits aninterrogating signal 1362 into the portion of subsurface vasculature anddetector 1350 is receiving a response signal 1352 generated in responseto the interrogating signal 1362. The response signal 1352 is related tothe binding of a clinically relevant analyte present in the subsurfacevasculature to the polyvalent functionalized magnetic particleconjugates 1340. As described above, in some embodiments, aninterrogating signal may not be necessary to generate a response signalrelated to the binding of an analyte to the polyvalent functionalizedmagnetic particle conjugates.

Both FIGS. 12B and 13B illustrate the path of the interrogating signal(1262, 1362) transmitted by the signal source (1260, 1360) and theresponsive signal (1252, 1352) detected by the detector (1250, 1350)essentially overlapping over a portion of subsurface vasculature. Insome examples, the signal source (1260, 1360) and the detector (1250,1350) may be angled towards each other so that they are interrogatingand detecting from essentially the same area of subsurface vasculature.However, in some instances, such as in the example shown in FIG. 11B,the paths of the interrogating signal (1262, 1362) transmitted by thesignal source (1260, 1360) and the responsive signal (1252, 1352)detected by the detector (1250, 1350) may not overlap.

VI. Illustrative Methods for Real-Time, High-Density Physiological DataCollection Using a Wrist Mounted Device

FIG. 14 is a flowchart of a method 1400 for using a wearable device totake real-time, high-density, non-invasive, in vivo measurements ofphysiological parameters. In a first step, the wearable deviceautomatically measures one or more physiological parameters during eachof a plurality of measurement periods (1410). The length of themeasurement period may be set on the device itself or may be setremotely, for example, by instruction from a remote server. The devicemay be configured with many measurement periods each day—for example,continuous, every second, every minute, every hour, every 6 hours,etc.—or may be configured to take measurements once a week or once amonth. Further, a different measurement period may be set for each ofthe physiological parameters being measured. The measurement periods mayextend through a plurality of consecutive days and each of theconsecutive days may include multiple measurement periods. Each of theconsecutive days may further include at least twenty-four measurementperiods and the plurality of consecutive days may include at leastthirty days. At least some of the physiological parameters are measuredby non-invasively detecting one or more analytes in blood circulating insubsurface vasculature proximate to the wearable device.

After conclusion of a measurement period, for each of the plurality ofmeasurement periods, the wearable device transmits to a server datarepresentative of the physiological parameters measured during thatmeasurement period (1420). The wearable device may be configured toautomatically transmit the data to a server, may be configured totransmit on command of the wearer, or may be configured to transmit oninstruction from a remote server. Further, the device may be configuredto automatically transmit the data at the end of each measurementperiod, or at some more frequent or infrequent rate. For example, thedevice could be configured to transmit every five minutes, at the end ofeach day, at the end of the month, at nighttime only, etc.

In response, the server is configured to develop a baseline profilebased on the data transmitted by the wearable device for the pluralityof measurement periods (1430). In some embodiments, the baseline profileincludes an individual baseline profile based on the data transmitted bythe wearable device for the plurality of measurement periods for anindividual user wearing the wearable device. As described above, thebaseline profile may include patterns for how one or more of thewearer's physiological parameters typically change over time, such asduring the course of a day, a week, or a month. The baseline profile mayfurther include threshold values of certain target analytes, above orbelow which a medical condition may be indicated.

After the server has developed an individual baseline profile for awearer of the device, the server may receive additional data regardingthe physiological parameters from the wearable device measured duringone or more additional measurement periods (1440). The server may thencompare the additional data, collected over additional measurementperiods, to the individual baseline profile. If the additional data isconsistent with the patterns embodied in the individual baselineprofile, the server may determine that the wearer's condition has notchanged. On the other hand, if the additional data deviates from thepatterns embodied in the baseline profile, the server may detect achange in the wearer's condition (1450). The change in condition could,for example, indicate that the wearer has developed a disease, disorder,or other adverse medical condition or may be at risk for a severemedical condition, such as a stroke or a heart attack, in the nearfuture.

If the server detects a change in condition based on the individualbaseline profile and the additional data, it may generate one or morerecommendations based on the detected change in condition and a clinicalprotocol (1460). For example, the server may generate a recommendationthat the wearer take a particular medication or supplement, schedule anappointment with a medical professional, go to the hospital to seekimmediate medical attention, abstain from certain activities, etc. Theserver may also be configured to receive data regarding physiologicalparameters measured by a plurality of wearable devices (1470) and usethat data to develop, at least in part, the clinical protocol. Theclinical protocol may also be developed based, at least in part, on anyknown health information or medical history of the wearer, and/or onrecognized standards of care in the medical field. The wearable devicemay receive the one or more recommendations generated by the server(1470) and providing an indication of the one or more recommendationsvia a user interface on the wearable device.

In some embodiments, the server may be configured to receive dataregarding physiological parameters measured by a plurality of wearabledevices. The server may use this data collected from a plurality ofwearable devices—worn by a plurality of users—to develop, at least inpart, a population baseline profile. Such population baseline profilesmay be used, for example, for comparison with an individual's baselineprofile. Those of skill in the art will readily recognize thatcomparison of an individual's physiological parameters measured overtime to that individual's own baseline may not be sufficient torecognize an abnormality in that physiological parameter. For example,while a physiological parameter for an individual wearer of the devicemay not deviate from that individual's baseline, that individualbaseline may be well above the population baseline generated from datacollected from a plurality of wearers of the device. Thus, comparison towhat is “normal” or “average” for a population may be necessary foreffective identification or prevention of a medical condition in anindividual.

Accordingly, the server may further be configured to receive from thewearable device additional data measured during one or more additionalmeasurement periods, detect a change in condition based on thepopulation baseline profile and the additional data, and generate one ormore recommendations based on the detected change in condition and aclinical protocol. The wearable device may receive the one or morerecommendations generated by the server and provide an indication of theone or more recommendations via a user interface on the wearable device.

In further embodiments, the method may include introducing polyvalentfunctionalized particle conjugates into the blood, wherein thepolyvalent functionalized magnetic particle conjugates are configured tobind to the one or more analytes. As shown in FIG. 15, the wearabledevice may non-invasively measure one or more analytes in bloodcirculating in subsurface vasculature proximate to the wearable deviceby directing, from a signal source in the wearable device, aninterrogating signal into the subsurface vasculature proximate to thewearable device (1510). As discussed above, this step may not benecessary in cases where the polyvalent functionalized particleconjugates generate a response signal related to binding of the one ormore analytes without the need for an interrogating signal. In any case,the wearable device may detect, with a detector, a response signaltransmitted from the subsurface vasculature proximate to the wearabledevice in response to the interrogating signal (1520). The responsesignal is related to binding of the one or more analytes to thepolyvalent functionalized particle conjugates. In examples where aninterrogating signal is used, the interrogating signal may include atime-varying magnetic field and the response signal may include anexternally-detectable physical motion due to the time-varying magneticfield. The interrogating signal may include an electromagnetic pulse(e.g., a radio frequency (RF) pulse) and the response signal may includea magnetic resonance (MR) signal. The interrogating signal may includeelectromagnetic radiation having a wavelength between about 400nanometers and about 1600 nanometers, more particularly, a wavelengthbetween about 500 nanometers and about 1000 nanometers. Where thepolyvalent functionalized particle conjugates also include afluorophore, the response signal may include fluorescence radiationtransmitted by the fluorophore in response to the interrogating signal.

In some examples, the polyvalent functionalized particle conjugates mayalso be magnetic. The process of measuring one or more analytes in bloodcirculating in subsurface vasculature may further include directing,from a magnet in the wearable device, a magnetic field into thesubsurface vasculature proximate to the wearable device (1530). Themagnetic field is sufficient to cause the polyvalent functionalizedmagnetic particle conjugates to collect in a lumen of the subsurfacevasculature proximate to the wearable device.

FIG. 16 is a flowchart of a method 1600 for using a wearable device totake real-time, high-density, non-invasive, in vivo measurements ofphysiological parameters. In a first step, the wearable deviceautomatically measures one or more physiological parameters during eachof a plurality of measurement periods (1610). The measurement periodsmay extend through a plurality of consecutive days, wherein each of theconsecutive days includes multiple measurement periods. At least some ofthe physiological parameters are measured by non-invasively detectingone or more analytes in blood circulating in subsurface vasculatureproximate to the wearable device.

Upon conclusion of a measurement period for each of the plurality ofmeasurement periods, the wearable device automatically wirelesslytransmits to a server data representative of the physiologicalparameters measured during that measurement period (1620). The servermay be configured to receive, upon conclusion of a measurement period,an indication of the health state of a user of the wearable device forthat measurement period and derive a correlation between the healthstate of the user and the data representative of the physiologicalparameters measured during that measurement period (1630). For example,the server may be configured to recognize patterns, for example, everytime a physiological parameter reaches or drops to a certain level, thewearer of the device indicates that he or she experiences a migraine.Recognition of these patterns or correlations may help medicalprofessionals to recognize, prevent, diagnose and/or treat of healthconditions in that individual. Further, the server may be configured touse these correlation to alert the user that a medical condition may beimminent.

A baseline profile may be developed by the server based on the datatransmitted by the wearable device for the plurality of measurementperiods (1650). The server may further be configured to receive from thewearable device additional data representative of the physiologicalparameters measured during one or more additional measurement periods(1660), detect a change in condition based on the baseline profile andthe additional data (1670), and generate one or more recommendationsbased on the detected change in condition and a clinical protocol(1680). The clinical protocol may be developed based, at least in part,on the derived correlation. For example, the clinical protocol mayindicate that a medical condition may be imminent based on a comparisonbetween current measurement of a physiological parameter and the derivedcorrelation between previously measured physiological parameters andpreviously reported health state.

In a further example, the server may be configured to receive dataregarding physiological parameters measured by a plurality of wearabledevices and receive an indication of the health state of the users ofthe plurality of wearable devices for a plurality of measurementperiods. The server may then derive a correlation between the healthstate of the users and the data representative of the physiologicalparameters measured during the plurality of measurement periods.Population data of this kind may be significant in that suchcorrelations may never before have been drawn between that physiologicalparameter and a particular health condition. Such correlations may beused in prediction, prevention, diagnoses and treatment of healthconditions. The server may also be configured to receive from thewearable device additional data representative of the physiologicalparameters measured during one or more additional measurement periodsand generate one or more recommendations based on the receivedadditional data and a clinical protocol, wherein the clinical protocolis developed based, at least in part, on the derived correlation.

In a further example, the wearable device itself may be configured toperform the steps described above as being performed by a remote server.For example, the wearable device may be configured to analyze the datarepresentative of the physiological parameters, generate a baselineprofile, compare data collected from additional measurement periods tothe baseline profile, and generate recommendations based on a clinicalprotocol. The wearable device may further be configured to transmit,either automatically or on some other frequency, certain data to theremote server.

VII. Illustrative Non-Invasive Analyte Detection System with ModulationSource

The signal-to-noise ratio (SNR) in an analyte detection system, such asany of those described above, may be increased by modulating the analyteresponse signal transmitted from the subsurface vasculature (or otherbody system) with respect to the background signal and, in some cases,an unbound particle response signal. Such modulation can increase thesystem's sensitivity and ability to discern between target analytespresent in the blood or other bodily fluids, versus other analytes,particles, cells, molecules, blood components, bone and tissues, etc.This can be particularly valuable with some methods of analytecharacterization, such as optical methods, or where the target analytesare rare in the blood or are of a relatively small size and withfluorescence detection techniques, which can often suffer from lowresolution because other tissues, cells, and molecules in the body mayhave some inherent fluorescent properties, creating a high level ofbackground noise.

FIGS. 17A-17B, which are partial cross-sectional side views of a humanwrist, illustrate the operation of an example system 1700 includingpolyvalent functionalized particle conjugates 1740 configured tointeract with one or more target analytes present in blood or otherbodily fluid, a detector 1750 configured to detect a response signal1752 transmitted form a portion of the body, such as the subsurfacevasculature, and a modulation source 1770 configured to modulate theresponse signal 1752. The polyvalent functionalized particle conjugates1740 may be introduced into the body, for example, into a lumen of thesubsurface vasculature 1730 by any known route, including orally,transdermally, topically, transmucosally, intramuscularly, etc. In someembodiments, the system 1700 may also include a signal source 1760, butas described above, an interrogating signal 1762 is not necessary inevery case to generate a response signal 1752. Further, in someembodiments, the signal source 1760 itself may be modulated (therebymodulating the response signal 1752 as well). In these embodiments, themodulation and interrogation are essentially combined.

In some embodiments, the system 1700 may be implemented with a wearabledevice 1710, which may include any device that is capable of being wornat, on or in proximity to a body surface, such as a wrist, ankle, waist,chest, or other body part. The wearable device 1710 may be positioned onor in proximity to a portion of the body where subsurface vasculature1730 (or other body system) is readily observable, so that analytemeasurements may be taken noninvasively from outside of the body. Thedevice 1710 may be placed in close proximity to the skin or tissue, butneed not be touching or in intimate contact therewith. Additionally oralternatively, the system 1700 may be implemented by implanting one ormore of the components, such as the detector 1750, signal source 1760and/or modulation source 1770 under the skin, at a position where thesubsurface vasculature, or other body system, is readily observable.System 1700 may also be implemented as a stationary device or as adevice which may be temporarily held against or in proximity to a bodysurface for one or more measurement periods.

A mount 1720, such as a belt, wristband, wristwatch, ankle band,headband, eyeglasses, necklace, earrings, etc. can be provided to mountor stabilize the device 1710 at, on or in proximity to a body surface.The mount 1720 may prevent the wearable device 1710 from moving relativeto the body to reduce measurement error and noise. Further, the mount1720 may be an adhesive substrate for adhering the wearable device tothe body of a wearer. The detector 1750, modulation source 1770,interrogation signal source 1760 (if applicable) and, in some examples,a processor (not shown), or portions thereof may be provided on thewearable device 1710. Mount 1720 may be designed such that device 1710may be worn continuously without interfering with the wearer's dailyactivities so that measurements may be taken throughout the day. Inother examples, the mount 1720 may be designed to temporarily hold thedevice 1710 on or near the body during measurement periods only. Each ofthe detector 1750, modulation source 1770 and signal source 1760 (ifapplicable) can be located proximal to one another on the same portionof the mount as shown in FIGS. 17A-17B, or can be positioned atdifferent locations on the mount 1720.

The state of the subsurface vasculature during a measurement period isillustrated in FIG. 17B. In this embodiment, signal source 1760transmits an interrogating signal 1762 into a portion of the body anddetector 1750 receives a response signal 1752 transmitted from the body.The response signal 1752 may include an analyte response signal, anunbound particle signal and a background signal. The analyte responsesignal is related to the interaction of a target analyte present in thebody with the polyvalent functionalized particle conjugates 1740 andmay, in some cases, be generated in response to an interrogating signal1762. As described above, in some embodiments, an interrogating signalmay not be necessary to generate a response signal related to thebinding of an analyte to the polyvalent functionalized particleconjugates. Further, in other examples, the modulation source mayessentially act as a signal source by generating a modulatedinterrogation signal.

The modulation source 1770 applies a modulation 1772, configured tomodulate the response signal, to the portion of the body. Specifically,the modulation source 1770 may be configured to modulate the analyteresponse signal differently from a background signal. The backgroundsignal may include any signal transmitted from something other than whatthe system 1700 is monitoring, i.e., the target analyte(s). In someexamples, the background signal may be generated by other molecules,cells, or particles in the blood or other bodily fluids; tissue, such asskin, veins, muscle, etc.; bone; or other objects present in thewearer's body. A background signal may be generated by excitation ofthese objects from the interrogating signal, such as by generating anautofluorescence signal, or due to some inherent property of theseobjects, such as, chemiluminescence, etc.

Both bound particles 1742 and unbound particles 1744 may be present inthe subsurface vasculature 1730 in the area of the wearable device 1710.“Bound” particles 1742 include any particles that are bound to orotherwise interacting with the target analyte(s). The analyte responsesignal is transmitted from these bound particles 1742. Conversely,“unbound” particles 1744 include any particles that are not bound to orotherwise interacting with the target analyte(s). The unbound particles1744 may produce an unbound particle signal (not shown) that is notrelated to the binding or interaction of the target analyte(s) with thepolyvalent functionalized particle conjugates 1740. In some examples,the modulation source 1770 may be configured to modulate the analyteresponse signal differently than the unbound particle signal, such thatthe analyte response signal may be differentiated from the unboundparticle signal. Such differentiation may be used to determine thenumber or percentage of particles 1740 bound to or interacting with thetarget analyte(s), which may be used to determine a concentration of thetarget analyte(s) in the blood or other bodily fluid, to determine ifand to what extent the particles are being cleared from the body, etc.

The modulation source 1770 may include any means for modulating theresponse signal 1752. In some cases, the analyte response signal may bemodulated differently than the background signal, and in other cases theanalyte response signal may be modulated differently than the unboundparticle signal, or both. For example, the modulation source 1770 may beconfigured to alter the analyte response signal by spatially modulatingthe bound particles 1742. The modulation source 1770 may be configuredto modulate the optical properties, including the fluorescence,luminescence or chemiluminescence of the bound particles 1742. Infurther examples, the modulation source 1770 may be configured to alterthe magnetic, electric, acoustic, chemical and/or physical properties ofthe bound particles 1742. The modulation source 1770 may be a physicalconstruct or it may be a signal or energy applied to the body, or acombination thereof. Accordingly, the modulation 1772 may includespatial, temporal, spectral, thermal, magnetic, optical, mechanical,electrical, acoustic, chemical, or electrochemical type of modulation orany combination thereof.

In one example, the modulation source 1770 may be configured tospatially modulate the analyte response signal. For example, a spatialmodulation may exploit the speed, rotation, size, thermodynamicproperties, hydrodynamic properties, etc. of the bound particles, versusunbound particles and other items that are not of interest, travellingwithin the vasculature 1730 to distinguish the analyte response signal.For example, an analyte-bound particle is going to have a different sizeand shape than an unbound particle and, therefore, may travel throughthe subsurface vasculature a different speed, thereby modulating betweenbound and unbound particles. In one example, analyte-bound magneticparticles may travel through the subsurface vasculature at a differentspeed when subject to a magnetic field than unbound magnetic particles.The modulation source 1770 may be used to exploit this difference inspeed to differentiate the analyte response signal from other signalstransmitted from the body.

Other forces, such as magnetic or acoustic forces, may be used toinfluence the spatial properties or motion of the particles through thevasculature, thereby further distinguishing between particles withdifferent hydrodynamic properties in the blood flow (e.g. large vs.,small, bound vs. unbound, shapes, buoyancy and the like). For example,magnetic particles will align and orient themselves in a static magneticfield, but Brownian motion will randomize their angular positions whenthe magnetic field is removed. The rate of randomization may depend onthe size and shape of the particle, i.e. on whether it is bound toanother object or not. Similarly, the rotational or translationalresponse of a particle to a time varying magnetic field may also dependon the size, shape and hence binding state of the particle. The size,shape or binding state dependency may manifest itself as a variation inmotion amplitude, as a variation in frequency response, as a phase shiftor combinations thereof. Other motive forces, such as acoustic forcesfor example, are also possible.

In general, spatial-modulation techniques may rely on observing thespatial response of particles when subjected to motive forces (magnetic,acoustic or other) in a hydrodynamic drag medium (e.g., blood). Both themotive force and the hydrodynamic drag force may be dependent on size,shape or binding state of the particle. Further, these techniques mayallow for measurement of the size/shape of the particle or the size ofthe object the particle is bound to. Exploitation of the motivedifferences may also allow for bound particles to be spatially separatedfrom unbound particles, or small particles from larger particles, orround particles from oblong particles etc. Spatial separation improvesthe signal to noise ratio for detecting particle properties and bindingstate.

In another example, the modulation 1772 may be based on the directmodulation of nanodiamond particles. Nanodiamonds are substances havingnitrogen point defects that will fluoresce in the near-IR range. Theintensity of the nanodiamond fluorescence can be influenced by amagnetic field—the higher the magnetic field, the lower thefluorescence. Accordingly, by exposing the nanodiamonds to a pulsedmagnetic field, the intensity of fluorescence can be modulated. Radiofrequency (RF) energy can also influence the intensity of fluorescence.

Thermal modulation may also be employed in some examples. Thermal energymay be used to cause a change a number of other particle characteristicsthat may be useful in modulating the analyte response signal, such as,fluorescence wavelength, fluorescence intensity, acoustic emissionfrequency or amplitude, or particle confirmation. These characteristicchanges may be used to differentiate the bound particles from unboundparticles and from background noise. In one example, an energy absorbingparticle may be irradiated with pulsed light or RF energy, causing anincrease in the particle's temperature. A rapid increase in temperaturemay cause the particle to expand and create an acoustic wave, which maybe detected by the detector 1750. Alternatively, rapid heating of theparticle above the boiling point of the surrounding liquid may cause agas bubble, the collapse of which upon cooling may produce a detectibleacoustic wave from cavitation. In another example, an increase intemperature may cause degradation or a change in conformation of theparticle, allowing some material, such as a fluorophore or contrastagent, to be released from a cavity inside the particle, thefluorescence of which may be detected by the detector 1750.

“Quenching fluorescence” is another type of thermal modulation that mayalso be used to modulate the response signal 1752. Quenching, whichrefers to any process which decreases the fluorescence intensity of agiven substance, is often heavily dependent on pressure and temperature.Förster resonance energy transfer (FRET), Fluorescence resonance energytransfer (FRET), resonance energy transfer (RET) or electronic energytransfer (EET), are mechanisms describing energy transfer between twochromophores and are all quenching mechanisms. A donor chromophore,initially in its electronic excited state, may transfer energy to anacceptor chromophore through nonradiative dipole-dipole coupling. Theefficiency of this energy transfer is inversely proportional to thedistance between donor and acceptor. The application of thermal energymay cause the chromophore pairs to pop apart or otherwise separate,thereby permitting each chromophore to fluoresce. This technique may beused to modulate the response signal 1752, in one example, byconfiguring the chromophore particles to couple together when bound toan analyte. Thermal, acoustic, magnetic or other energy, may also beused to cause the reversible thermal denaturation or modulation of anreceptor or protein complex, where there is one bright confirmation andone quenched confirmation.

In another embodiment, an external energy, such as a magnetic field, maybe used to spatially modulate the particles to differentiate the analyteresponse signal from the unbound particle signal and background noise.Some type of external energy may be applied to the subsurfacevasculature 1730 to cause some type of observable movement or motion inthe bound particles 1742, i.e., linear motion, rotation, etc. If aparticle is bound to or interacting with a target analyte, its physicalmotion will be affected in response to the modulation 1772, for example,it may translate or rotate slower than unbound particles. Thus, boundparticles 1742 will behave differently than the unbound particles 1744and any other objects present in the body. Alternatively, the particles'response once released from the modulation 1772 may also be observed.For example, bound particles 1742 may take longer to return to normalvelocity or normal rotation than unbound particles 1744 once themodulation source 1770 is turned off.

Time-domain separation may also be used to modulate the response signal1752. For example, modulation may be achieved by exploiting the varyingfluorescence lifetimes of different fluorophores. The exponential decayin fluorescence of a particular fluorophore can be observed uponextinguishing the excitation light. In one example, polyvalentfunctionalized particle conjugates may be composed from or include afluorescent material that has a much longer fluorescence lifetime thanthe fluorescence lifetime of those objects that make up the backgroundsignal. Upon extinguishing the excitation signal, the system will delaydetection of the signal generated by the bound particles 1742 untilafter the decay of the background fluorescence, thereby allowing theanalyte response signal to be distinguished from the background.Fluorescence of the bound particles 1742 may also be modulated bydriving the excitation light at certain frequencies or by exploiting thephosphorescence or chemiluminescence lifetimes of different particles.In another example, time-of-flight or a time-of-flight camera may beused to detect a modulated response signal 1752.

In another embodiment, optical analytical methods can be used tomodulate the response signal 1752. For example, confocal microscopy maybe used to eliminate or diminish the background signal by selectingphotons that originate only from a sharp focal area. To this end, boundparticles 1742 may be mechanically modulated in and out of the focalarea to achieve a periodically modulated fluorescence signal. Otheroptical techniques may be used for eliminated or reducingcharacteristics of the background, such as, optical coherence tomography(OCT), wavelength filtering, polarization, phase conjugate despeckling,and phase contrast.

In another embodiment, nuclear magnetic resonance (NMR) may be used tomodulate the response signal 1752. Both frequency of precession andmagnetic relaxation lifetimes techniques may be used to measure theresponse of the bound particles 1742 themselves or of their surroundingenvironment. In general, an RF field is applied to the subsurfacevasculature 1730, causing it to emit a magnetic resonance signal at acertain frequency. The characteristics of the particles or other objectsin the sample, or the surrounding environment, are observed as theyreturn/relax to their lower energy state. The behavior of boundparticles 1742 will be different than the unbound particles 1744 and thebackground.

The elements of the system, namely the type of applied modulation 1772,the type/shape/materials of particles 1740, types of receptors andtarget analytes may all be interrelated. Ultimately, the type ofparticle 1742 and receptor used to detect a particular target analyte1740 may be dictated, to some extent, by the characteristics of thetarget analyte (i.e., type, size, shape, affinities, etc.), the chosentype of modulation 1772 (i.e., spatial, spectral, thermal, magnetic,mechanical, chemical, etc.), and the mode of interrogation (optical,acoustic, magnetic, RF, etc.). Combinations of all of the abovemodulation techniques may also be used.

FIG. 18 is a simplified block diagram illustrating the components of anexample system 1800, including a wearable device 1810. Wearable device1810 may take the form of or be similar to one of the wrist-mounteddevices 200, 300, 400, 500, 600, or 1710 shown in FIGS. 2A-B, 3A-3C,4A-4C, 5, 6 and 17A-17B. However, wearable device 1810 may also takeother forms, such as an ankle, waist, ear, eye or chest-mounted device.Further, any of devices 200, 300, 400, 500, 600 and 1710 may beconfigured similar to or include any of the components of system 1800,including wearable device 1810.

In particular, FIG. 18 shows an example of a system 1800 including awearable device 1810 having a detector 1812, in some examples, a signalsource 1814, a modulation source 1816, and a communication interface1820, controlled by a controller 1830. Communication interface 1820 mayinclude an antenna. The components of the wearable device 1810 may bedisposed on a mount (not shown) for mounting the device to an externalbody surface where a portion of subsurface vasculature is readilyobservable. System 1800 may further include a remote device 1840 incommunication with the wearable device 1810, including a processor 1850,a computer readable medium 1860, a user interface 1870, and acommunication interface 1880 for communicating with the wearable device1810 and/or for transmitting data to a server or other remote computingdevice. While FIG. 18 depicts various components of system 1800 disposedon the wearable device 1810 or the remote device 1840, one of ordinaryskill in the art would understand that different configurations anddesigns are possible, including where all of the components are providedon the wearable device.

Processor 1850 may be a general-purpose processor or a special purposeprocessor (e.g., digital signal processors, application specificintegrated circuits, etc.) and can be configured to executecomputer-readable program instructions 1862 that are stored in thecomputer readable medium 1860 and are executable to provide thefunctionality of a system 1800 as described herein. The computerreadable medium 1860 may include or take the form of one or morenon-transitory, computer-readable storage media that can be read oraccessed by the processor 1850, and can include volatile and/ornon-volatile storage components, such as optical, magnetic, organic orother memory or disc storage, which can be integrated in whole or inpart with the processor 1850. The controller 1830 may be configured tooperate one or more of the detector 1812, signal source 1814 andmodulation source 1816. For example, the controller 1830 may activatethe detector 1812, signal source 1814 and modulation source 1816 duringeach of the pre-set measurement periods.

The program instructions 1862 stored on the computer readable medium1860 may include instructions to perform or facilitate some or all ofthe system functionality described herein. For instance, in theillustrated embodiment, program instructions 1862 may includeinstructions for controller 1830 to operate the detector 1812, signalsource 1814 and modulation source 1816. Program instructions 1862 mayfurther cause the processor 1850 to detect the one or more targetanalytes by differentiating the analyte response signal from thebackground signal based, at least in part, on a modulation applied bythe modulation source 1816. In some cases, the processor may further beconfigured to differentiate the analyte response signal from the unboundparticle signal. Further, the processor 1850 may be configured todetermine the concentration of a particular target analyte in the bloodfrom, at least in part, the analyte response signal. The detection andconcentration data processed by the processor may be communicated to thepatient, for example via the user interface 1870, transmitted to medicalor clinical personnel, locally stored or transmitted to a remote server,the cloud, and/or any other system where the data may be stored oraccessed at a later time. The program instructions 1862 may also includeinstructions for operating a user interface 1870, for example,instructions for displaying data transmitted from the wearable device1810 and analyzed by the processor 1850, or for generating one or morealerts.

VIII. Illustrative Method for Modulation of a Response Signal toDistinguish Between Analyte and Background Signals

FIG. 19 is a block diagram of an example method (1900) for modulating aresponse signal. Polyvalent functionalized particle conjugates areintroduced into a living body, such as, into a lumen of subsurfacevasculature (1910). The particles may be introduced into the blood orsome other bodily fluid or system, including the lymphatic system, thedigestive system, the nervous system, etc. The polyvalent functionalizedparticle conjugates may also be embedded in skin or tissue of the bodyand may be configured to interact with target analytes present in theskin or tissue. Introduction of the polyvalent functionalized particleconjugates into the body may be achieved by any of the means describedabove, including transdermally, transmucosally, topically,intravenously, intramuscularly, and orally. For example, polyvalentfunctionalized particle conjugates may be introduced into the bloodthrough use of a swallowable capsule designed to deliver polyvalentfunctionalized particle conjugates into the intestinal wall.

The polyvalent functionalized particle conjugates may be configured tointeract with one or more target analytes present in the body, such asthose present on surfaces of cells circulating in blood in subsurfacevasculature. The particles may take any of the forms or have any of thecharacteristics, or combinations thereof, described above. In general,the particles will be inherently designed to interact with a particulartype target analyte or be functionalized with an receptor that has aspecific affinity for a target analyte. A plurality of types ofpolyvalent functionalized particle conjugates may be introduced into thebody, each type having an affinity for a specific target analyte.

According to the example method (1900), the one or more target analytesmay be detected (1920) by, in a first step, detecting a response signaltransmitted from the body, which includes a background signal and ananalyte response signal (1930). The analyte response signal is relatedto interaction of the polyvalent functionalized particle conjugates withthe one or more target analytes. In some examples, the response signalis transmitted from the subsurface vasculature. As described above, insome cases, an interrogating signal may also be directed into the body.The response signal, in such cases, may be generated, at least in part,in response to the interrogating signal and may then be detected. Amodulation, configured to alter the response signal such that theanalyte response signal is affected differently than the backgroundsignal, may be applied to a portion of the body (1940), such as thesubsurface vasculature. The analyte response signal may then bedifferentiated from the background signal (1950).

The response signal may further include an unbound particle signalrelated to polyvalent functionalized particle conjugates that are notinteracting with the one or more target analytes. In some examples, themodulation may also be configured to alter the response signal such thatthe analyte response signal is affected differently than the unboundparticle signal and the background signal, thereby allowing the analyteresponse signal to be differentiated from the unbound particle signaland the background signal.

The modulation may be configured to alter the response signal byspatially modulating the polyvalent functionalized particle conjugatesthat are interacting with the one or more target analytes. In otherexamples, the modulation may be configured to alter the response signalby modulating optical properties of those polyvalent functionalizedparticle conjugates that are interacting with the one or more targetanalytes, including their fluorescence, luminescence orchemiluminescence. In other examples, the modulation may be configuredto alter the response signal by modulating magnetic, electric, acoustic,chemical and/or physical properties of those polyvalent functionalizedparticle conjugates that are interacting with the one or more targetanalytes.

IX. Illustrative System and Method for Spatial Modulation of a ResponseSignal by an External Magnetic Field Using Magnetic Particles

FIGS. 20A-20E illustrate one embodiment of an illustrative system 2000for spatially modulating a response signal. The example system 2000includes polyvalent functionalized particle conjugates 2040 configuredto interact with one or more target analytes present in blood or otherbodily fluid, one or more detectors 2050 configured to detect a responsesignal 2052 transmitted from a portion of the body, such as thesubsurface vasculature 2030, and a modulation source 2070 configured tomodulate the response signal 2052. The polyvalent functionalizedparticle conjugates 2040 may be introduced into the body, for example,into a lumen of the subsurface vasculature 2030 by one of the meansdiscussed above. As illustrated in FIG. 20A, the detector(s) 2050 andthe magnetic field source(s) 2072 may respectively be provided as anarray of connected elements, the utility of which will be describedfurther below. Alternatively, the detector(s) 2050 and the magneticfield source(s) 2072 may each be provided as single elements.

Similar to system 1700 described above, the system 2000 may beimplemented with a wearable device 2010, which may include any devicethat is capable of being worn at, on or in proximity to a body surface,such as a wrist, ankle, waist, chest, or other body part. In the exampleshown in FIG. 20A, which is a partial cross-sectional side view of ahuman wrist, the wearable device 2010 may be provided as a wrist-mounteddevice. A mount 2020, such as a belt, wristband, wristwatch, ankle band,headband, eyeglasses, necklace, earrings, etc. can be provided to mountor stabilize the device at, on or in proximity to the body surface. Inthe present example, mount 2020 is provided as strap or wrist-band tosecure the device 2010 on a wearer's wrist. As described above withrespect to system 1700, system 2000 may also include a processor (notshown) configured to non-invasively detect the presence and/orconcentration of the one or more target analytes.

Both bound particles 2042—those polyvalent functionalized particleconjugates interacting with the target analytes—and unbound particles2044—those polyvalent functionalized particle conjugates not interactingwith the target analytes—may be present in the subsurface vasculature2030 in the area of the wearable device 2010. The modulation source 2070may include any means for modulating the response signal 2052, which mayinclude an analyte response signal 2054, an unbound particle signal 2056and a background signal (not shown). For example, the modulation source2070 may be configured to both modulate the analyte response signal 2054differently than the unbound particle signal 2056, such that the analyteresponse signal may be differentiated from the unbound particle signal,and to modulate the analyte response signal 2054 from the background.

As shown in FIGS. 20B and 20C, the modulation source 1770 may beconfigured to alter the analyte response signal 2054 and the unboundparticle signal 2056 by spatially modulating the bound particles 2042and the unbound particles 2044 with a mask 2076 having a spatialarrangement. The modulation source 2070 may include magnetic particles2074, introduced into the subsurface vasculature 2030, and one or moremagnetic field sources 2072, sufficient to distribute the magneticparticles 2074 into a spatial arrangement in a lumen of the subsurfacevasculature 2030. The magnetic field source(s) 2072 may include, forexample, an array of permanent magnets, field concentrating materialsand shielding materials, or thin film materials.

In one example, the magnetic particles 2074 may be manipulated to form amask 2076, as shown in FIG. 20B, on an inner surface of the lumen of thesubsurface vasculature 2030, for spatial modulation of the responsesignal 2052. As shown in FIG. 20C, when the magnetic field source(s)2072 are activated, the magnetic particles 2074 may aggregate in theareas of the concentrated magnetic field(s) on an inner surface of thelumen of the subsurface vasculature 2030 closes to the detector(s) 2050.Accordingly, the shape of the mask may be determined based on thespatial shape or distribution of the magnetic fields created by themagnetic field source(s) 2072. For example, the mask 2076 may be in theshape of several bars oriented essentially perpendicular to the flow offluid in the vessel (F) and formed by an array of magnetic field sources2072 of similar shape. In some examples, the bars of the mask 2076 maybe spaced up to approximately 1 millimeter apart.

As shown in FIG. 20C, the mask 2076 acts to block or otherwise diminishthe response signal 2052 from reaching the detector(s) 2050 in the areain which it forms. When analyte-bound particles 2042, unbound particles2044, and any other materials (which may create a background signal)pass through the vasculature 2030 over the mask, the intensity of theresponse signal 2052 will essentially “blink” or pulse. In operation,different materials passing through the vasculature will be of differentsizes and shapes and, therefore, will pass through the vasculature 2030at different speeds. For example, the bound particles 2042 will, intheory, be larger and heavier than the unbound particles 2044.Accordingly, the bound particles 2042 will pass over the mask 2076 at aslower speed than the unbound particles 2044 and, therefore, the analyteresponse signal 2054 will “blink” at a lower frequency than the unboundparticle signal 2056, providing one level of distinction. Moreover, thebound particle signal 2054 will “blink” at a different frequency thanthe background signal.

This concept is also illustrated in FIGS. 21A and 21B, with a singleanalyte bound particle 2042 passing through the vasculature in thedirection of blood flow (F). Moving from left to right in the directionof blood flow (F), the analyte response signal 2054 will initially bedetected by a first element of the detector 2050. Depending on the typeof particle 2040, the target analyte, and the type of interaction orassociation between the target analyte and the particle 2040, theanalyte response signal 2054 may be of many different types. Forexample, in embodiments where the particle 2040 includes a fluorophore,or the interaction between the particle and the target analyte generatesa fluorescence, the analyte response signal 2054 may be an opticalsignal. As the bound particle 2042 processes (as shown in dotted lines),the analyte response signal 2054 will then be blocked or diminished bythe magnetic particles 2074 forming the mask 2076 in the vasculature,whereby little or no analyte response signal 2054 will reach thedetector 2050. Thus, as the bound particle 2042 continues through thevasculature, passing over each segment of the mask 2076, the analyteresponse signal 2054 will be periodically blocked or diminished, whichmay be observed as a “blinking” of the signal. Other forces, such asmagnetic or acoustic forces, may be used to influence the motion of theparticles through the mask area, thereby further distinguishing betweenparticles with different hydrodynamic properties in the blood flow (e.g.large vs., small, bound vs. unbound, shapes, buoyancy and the like).

FIG. 21B is a graphical representation of the analyte response signal2054 intensity (I) plotted against time (t). This Figure is illustrativeof the “blinking” signal which may be sensed by the detector 2054. Inoperation, different items present in the vasculature, i.e., unboundparticles 2044, cells, other molecules, will “blink” at a differentfrequency, producing a different signal, having a different period. Tothis end, bound particles 2042 may be differentiated from other objectspresent in the blood.

In the embodiments shown in FIGS. 20A-20C and 21A-21B, a mask 2076 isformed on the inside of a vessel 2030 by manipulating magnetic particles2074, introduced into the subsurface vasculature, with an externalmagnetic field source 2072. By forming the mask on the inside of thevessel, dispersion caused by intervening tissue, which might otherwiseoccur if the mask were placed external to the body, may be reduced.Periodic mechanical (e.g. acoustic) perturbation may “sharpen” the bandsof the mask by adding energy to reduce non-specific aggregation of themagnetic particles.

FIG. 22 is a flow chart of an exemplary method 2200 for analytedetection by spatially modulating are response signal with an internallyapplied mask. In a first step, polyvalent functionalized particleconjugates are introduced into a lumen of subsurface vasculature (2210).The polyvalent functionalized particle conjugates may be configured tointeract with one or more target analytes present on cells in blood (ortear fluid, urine, lymph, cerebrospinal fluid, stool, mucus, or otherbody fluid) circulating in the subsurface vasculature (or other bodysystem). Magnetic particles may also be introduced into the subsurfacevasculature (2220) and a magnetic field, sufficient to distribute themagnetic particles into a spatial arrangement in a lumen of thesubsurface vasculature, may be applied (2230). A response signal,including a background signal and an analyte response signal,transmitted from the subsurface vasculature is detected (2240). Theanalyte response signal is related to interaction of the polyvalentfunctionalized particle conjugates with the one or more target analytesand may be modulated with respect to the background signal due, at leastin part, to the spatial arrangement of the magnetic particles. The oneor more target analytes may be detected by differentiating the analyteresponse signal from the background signal due, at least in part, to themodulation of the analyte response signal (2250).

The response signal may further include an unbound particle signalrelated to polyvalent functionalized particle conjugates that are notinteracting with the one or more target analytes. The one or more targetanalytes may be non-invasively detected by differentiating the analyteresponse signal from the background signal and the unbound particlesignal due, at least in part, to the modulation of the analyte responsesignal. The analyte response signal is modulated differently than thebackground signal, in some cases, due, at least in part, to the velocityof the polyvalent functionalized particle conjugates in the bloodcirculating in the subsurface vasculature. The analyte response signalmay also be modulated differently than the unbound particle signal, insome cases, due, at least in part, to a difference in the velocity ofthe polyvalent functionalized particle conjugates in the bloodcirculating in the subsurface vasculature and the velocity of theunbound polyvalent functionalized particle conjugates.

X. Illustrative System and Method for Spatial Modulation of a ResponseSignal Using a Mask External to the Vasculature

In another example system 2300, shown in FIGS. 23A and 23B, themodulation source 2370 may employ a signal-blocking or diminishing mask2476 placed externally to the subsurface vasculature 2330. The mask 2476may be positioned anywhere between the subsurface vasculature 2330 orother body system or tissue in which the polyvalent functionalizedparticle conjugates 2340 have been introduced and a detector 2350, forexample, against an external surface of the body, imbedded in the skinor other tissue, or applied directly to the surface of the detector2350. Detector 2350 may be provided as part of a wearable device 2310,which may include a mount 2330, such as a strap for holding the device2310 against a body surface, such as a wrist. Similar to mask 2076 usedin system 2000 as shown in FIG. 20B, mask 2476 may be configured toalter the analyte response signal 2354 and the unbound particle signal2356 by spatially modulating the bound particles 2342 and the unboundparticles 2344 with a mask 2476 having a spatial arrangement. Forexample, the mask 2476 may be in the shape of several bars orientedessentially perpendicular to the flow of fluid in the vessel (F) thatare spaced up to approximately 1 millimeter apart.

As shown in FIG. 23B, the external mask 2476 may block or diminish theanalyte response signal 2354, the unbound particle signal 2356 and anybackground signal (not shown) from reaching the detector 2350. Similarto the discussion provided above with respect to system 2000, thespatial arrangement of the mask 2476 acts to modulate the analyteresponse signal 2354 with respect to the background signal and/or theunbound particle signal 2356. Because the bound particles 2342 will havedifferent hydrodynamic properties than the unbound particles 2344 andthose objects that produce the background signal, the bound particlesignal 2354 will be modulated differently than the unbound particlesignal 2356 and/or the background signal. The one or more targetanalytes may be detected by differentiating the analyte response signal2354 from the background signal due, in least in part, to the modulationof the analyte response signal 2354 by the mask 2376.

In another example illustrated in FIGS. 24A and 24B, the polyvalentfunctionalized particle conjugates 2440 of system 2400 may be magnetic.As described above, the polyvalent functionalized magnetic particleconjugatess 2440 may be formed of a magnetic material (i.e., a materialthat responds to a magnetic field) or may be functionalized with amagnetic material. The modulation source 2470 may employ asignal-blocking or diminishing mask 2476 placed externally to thesubsurface vasculature 2430 and may include an external magnetic fieldsource 2472. The external magnetic field source 2472 may be positionedon a wearable device 2410, such as a wrist-mountable device, having amount 2420 for securing the device against a body surface, along with adetector 2450. In operation, a magnetic field may be applied by magneticfield source 2472 to the subsurface vasculature 2430 sufficient to drawthe polyvalent functionalized-magnetic particle conjugates towards thesurface of the lumen of subsurface vasculature 2430 closest to the mask,as shown in FIG. 24B.

As compared to using an external mask, by using an internal mask, theresponse signal may be modulated at a location that has less scatteringmedium between the source (i.e., the polyvalent functionalized particleconjugates) and the point of modulation (i.e., the mask). With aninternal mask, the unmodulated light is scattered by blood but not byvasculature wall and skin. As shown in FIGS. 20A-20C, light travelingfrom the particles 2040, both bound 2042 and unbound 2044, to thedetector 2050 is spatially scattered by the dispersive tissue (blood,vein, skin) that is present between particle and detector, which mayreduce the signal to noise ratio. With an external mask as shown inFIGS. 23A and 23B, both the unmodulated and the modulated light may bescattered by blood, vasculature wall and skin. This scattering may bemitigated, as shown in FIG. 24B, by moving the particles towards themost superficial surface of the vein (e.g., closer to the detector2450), as described with respect to system 2400, so as to eliminate mostof the scattering from blood, which is a larger contributor toscattering than tissue. Acoustic, magnetic or other forces may be usedto move particles towards the most superficial wall of the vasculature.

As an alternative to using a physical mask (either internal orexternal), spatial modulation may be achieved with structuredillumination or structured detection. In the case of structuredillumination, light stripes or spots generated with spaced apart lightsources (LEDs or laser diodes, e.g.) or scanned light lines or projectedlight patterns, combined with broad detection may achieve spatialmodulation of the particle response signal. With a structured detectiontechnique, a broad illumination source is used in combination withspatially separated line or point detectors, or a pixelated detectorarray. Combinations of all of the above techniques may also be used.

In another embodiment shown in FIGS. 25A and 25B, system 2500 may employmagnetic polyvalent functionalized particle conjugates 2540 and amodulation source 2570 having a signal-blocking or diminishing mask 2576placed externally to the subsurface vasculature 2530, similar to system2400. Magnetic field source 2572, in this example, may be positioned ona wearable device 2510, such as a wrist-mountable device, having a mount2520 for securing the device against a body surface, upstream from thedetector 2550, at a point A. Using an external magnetic field generatedby magnetic field source 2572, the polyvalent functionalized particleconjugates 2540 may be retained against the upper wall of the vein forsome amount of time at a point A and then released back into the bloodflow. The response signal from the particles, including the analyteresponse signal 2554, the unbound particle signal 2556 and thebackground signal (not shown), may be detected a short distancedownstream from their point of release (so that they are still close tothe vein wall, but have picked up velocity in the blood stream) at apoint B. The response signal may be spatially modulated by the mask2576, which may act to distinguish the bound particles 2542 and unboundparticles 2544, having different hydrodynamic properties, on the basisof speed. After the magnetic field source 2572 is deactivated and theparticles are released, the resulting speed of the bound particles 2542will be different, and therefore detectable, over the speed of theunbound particles 2544 and other objects in the blood.

FIG. 26 is a flow chart of an exemplary method 2600 for analytedetection by spatially modulating a response signal with an externallyapplied magnetic field. Polyvalent functionalized magnetic particleconjugates configured to interact with one or more target analytespresent in blood circulating in the subsurface vasculature areintroduced into a lumen of subsurface vasculature (2610). A mask, havinga spatial arrangement, is applied externally to the subsurfacevasculature (2620). A magnetic field sufficient to draw the polyvalentfunctionalized magnetic particle conjugates towards a surface of thelumen of subsurface vasculature closest to the mask is applied (2630). Aresponse signal, which includes a background signal and an analyteresponse signal, transmitted from the subsurface vasculature may bedetected (2640). The analyte response signal is related to interactionof the polyvalent functionalized magnetic particle conjugates with theone or more target analytes and is modulated with respect to thebackground signal due, at least in part, to the spatial arrangement ofthe mask. The one or more target analytes may be non-invasively detectedby differentiating the analyte response signal from the backgroundsignal due, at least in part, to the modulation of the analyte responsesignal (2650). In some examples, an interrogating signal may also bedirected into the subsurface vasculature and a response signaltransmitted from the subsurface vasculature in response to theinterrogating signal may be detected.

The response signal may further include an unbound particle signalrelated to polyvalent functionalized particle conjugates that are notinteracting with the one or more target analytes. The target analytesmay be detected by differentiating the analyte response signal from thebackground signal and the unbound particle signal due, at least in part,to the modulation of the analyte response signal. The analyte responsesignal may be modulated differently than the background signal.Additionally or alternatively, the analyte response signal may bemodulated differently than the unbound particle signal.

In other exemplary methods, the magnetic field may be applied at a firstlocation with respect to the subsurface vasculature and the mask may beapplied at a second location with respect to the subsurface vasculature.The second location may be downstream of the first location in thedirection of the flow of blood circulating in the subsurfacevasculature. In such methods, the magnetic field may subsequently bedeactivated and a response signal transmitted from the subsurfacevasculature may be detected at the second location.

XI. Conclusion

Where example embodiments involve information related to a person or adevice of a person, some embodiments may include privacy controls. Suchprivacy controls may include, at least, anonymization of deviceidentifiers, transparency and user controls, including functionalitythat would enable users to modify or delete information relating to theuser's use of a product.

Further, in situations in where embodiments discussed herein collectpersonal information about users, or may make use of personalinformation, the users may be provided with an opportunity to controlwhether programs or features collect user information (e.g., informationabout a user's medical history, social network, social actions oractivities, profession, a user's preferences, or a user's currentlocation), or to control whether and/or how to receive content from thecontent server that may be more relevant to the user. In addition,certain data may be treated in one or more ways before it is stored orused, so that personally identifiable information is removed. Forexample, a user's identity may be treated so that no personallyidentifiable information can be determined for the user, or a user'sgeographic location may be generalized where location information isobtained (such as to a city, ZIP code, or state level), so that aparticular location of a user cannot be determined. Thus, the user mayhave control over how information is collected about the user and usedby a content server.

While various aspects and embodiments have been disclosed herein, otheraspects and embodiments will be apparent to those skilled in the art.The various aspects and embodiments disclosed herein are for purposes ofillustration and are not intended to be limiting, with the true scopebeing indicated by the following claims.

What is claimed is:
 1. A system comprising: polyvalent functionalizednanoparticles for binding with one or more target analytes on a surfaceof a cell present in an environment; a detector for detecting: ananalyte response signal transmitted from the environment, wherein theanalyte response signal is related to binding of the one or more targetanalytes on the cell surface with the polyvalent functionalizednanoparticles; and an unbound polyvalent functionalized nanoparticlesignal transmitted from the environment related to polyvalentfunctionalized nanoparticles that are not interacting with the one ormore target analytes; a modulation source for modulating the analyteresponse signal and the unbound nanoparticle signal, such that theanalyte response signal is affected differently than the unboundnanoparticle signal; and a processor for non-invasively detecting theone or more target analytes on the cell surface by differentiating theanalyte response signal from the unbound nanoparticle signal, based, atleast in part, on the modulation, wherein the modulation source altersone or more properties of the polyvalent functionalized nanoparticlesthat are bound to the one or more target analytes on the cell surfaceand wherein the one or more properties of the polyvalent functionalizednanoparticles comprises one or more of: optical properties, magneticproperties, electric properties, thermal properties, acousticproperties, chemical properties, and physical properties.
 2. The systemof claim 1, wherein the environment is a living body and furthercomprising a wearable device having a mount for mounting the wearabledevice to an external surface of the living body, wherein the detectoris mounted on the wearable device.
 3. The system of claim 2, wherein atleast a portion of the modulation source is mounted on said wearabledevice.
 4. The system of claim 1, wherein the processor furtherdifferentiates the analyte response signal from a background signal andwherein said modulation source modulates the analyte response signal andthe background signal, such that the analyte response signal is affecteddifferently than the background signal, or to alter the analyte responsesignal by spatially modulating the polyvalent functionalizednanoparticles that bind with the one or more target analytes on the cellsurface.
 5. The system of claim 1, wherein the modulation source altersthe analyte response signal by modulating an interrogation signaldirected into the body.
 6. The system of claim 1, further comprising aninterrogating signal source, the analyte response signal beingtransmitted in response to the interrogating signal.
 7. The system ofclaim 1, wherein the environment comprises a fluid conduit or a fluidreservoir.
 8. The system of claim 1, wherein the environment is a livingbody, wherein the polyvalent functionalized nanoparticles are introducedinto the living body to bind with one or more target analytes present ona surface of a cell in a body fluid contained in the living body, andwherein the body fluid comprises blood, tear fluid, urine, lymph,cerebrospinal fluid, stool, or mucus.
 9. The system of claim 1, whereinthe environment is a living body, wherein the polyvalent functionalizednanoparticles are embedded in skin or tissue of the living body, andwherein the functionalized nanoparticles are introduced into the livingbody to bind with one or more target analytes present on the surface ofa cell in the skin or tissue of the living body.
 10. A system,comprising: polyvalent functionalized nanoparticles for binding with oneor more target analytes on a surface of a cell present in anenvironment; a detector for detecting a response signal transmitted fromthe environment, wherein the response signal includes a backgroundsignal and an analyte response signal related to binding of the one ormore target analytes with polyvalent functionalized nanoparticles;magnetic particles; a magnetic field source sufficient to distribute themagnetic particles into a spatial arrangement in the environment,wherein the spatial arrangement of the magnetic particles modulates theanalyte response signal, such that the analyte response signal isaffected differently than the background signal; and a processor fornon-invasively detecting the one or more target analytes bydifferentiating the analyte response signal from the background signalbased, at least in part, on modulation of the analyte response signal,wherein the analyte response signal is modulated differently than thebackground signal or modulated differently than the unbound particlesignal.
 11. The system of claim 10, wherein the response signal furtherincludes an unbound particle signal related to polyvalent functionalizednanoparticles that are not bound with the one or more target analytes.12. The system of claim 11, wherein the processor further non-invasivelydetects the one or more target analytes by differentiating the analyteresponse signal from the unbound particle signal, at least in part,based on modulation of the signals due, at least in part, to the spatialarrangement of the magnetic particles.
 13. The system of claim 10,further comprising an interrogating signal source, the response signalbeing transmitted in response to the interrogating signal.
 14. Thesystem of claim 10, wherein the environment comprises a fluid conduit orfluid reservoir.
 15. The system of claim 13, wherein the environmentcomprises a living body.
 16. The system of claim 15, wherein theenvironment comprises a lumen of subsurface vasculature in the livingbody.
 17. A method comprising: introducing polyvalent functionalizednanoparticles into an environment for binding with one or more targetanalytes on a surface of a cell present in the environment; detecting ananalyte response signal transmitted from the environment, wherein theanalyte response signal is related to binding of the one or more targetanalytes with the polyvalent functionalized nanoparticles and whereinthe response signal is modulated; detecting an unbound polyvalentfunctionalized nanoparticle signal transmitted from the environment,wherein the unbound nanoparticle signal is related to polyvalentfunctionalized nanoparticles that are not interacting with the one ormore target analytes; detecting a background signal; applying amodulation to a portion of the environment for altering the analyteresponse signal and the unbound nanoparticle signal, such that theanalyte response signal is affected differently than the unboundnanoparticle signal and the background signal; and differentiating theanalyte response signal from the unbound nanoparticles signal and thebackground signal.
 18. The method of claim 17, further comprising:directing an interrogating signal into the environment; and detectingthe analyte response signal transmitted from the environment in responseto the interrogating signal.
 19. The method of claim 17, wherein theenvironment comprises a fluid conduit, a fluid reservoir, or a livingbody.
 20. The method of claim 19, wherein the polyvalent functionalizednanoparticles interacts with one or more target analytes present in theliving body.
 21. The method of claim 20, wherein the polyvalentfunctionalized nanoparticles are embedded in skin or tissue of theliving body.
 22. The method of claim 21, wherein the polyvalentfunctionalized nanoparticles interacts with one or more target analytespresent in the skin or tissue of the living body.
 23. The systemaccording to claim 1, wherein the cells are tumor cells.
 24. The systemaccording to claim 10, wherein the cells are tumor cells.
 25. The methodaccording to claim 17, wherein the cells are tumor cells.
 26. The systemof claim 1, wherein the nanoparticles comprise two or more differentbinding receptors to detect multiple different target analytes on thecell surface.